IL263224B1 - Use of a histone deacetylase inhibitor and a population of inactivated pluripotent cells for treating cancer - Google Patents
Use of a histone deacetylase inhibitor and a population of inactivated pluripotent cells for treating cancerInfo
- Publication number
- IL263224B1 IL263224B1 IL263224A IL26322418A IL263224B1 IL 263224 B1 IL263224 B1 IL 263224B1 IL 263224 A IL263224 A IL 263224A IL 26322418 A IL26322418 A IL 26322418A IL 263224 B1 IL263224 B1 IL 263224B1
- Authority
- IL
- Israel
- Prior art keywords
- cells
- cancer
- population
- pluripotent
- cell
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 164
- 201000011510 cancer Diseases 0.000 title claims description 90
- 239000003276 histone deacetylase inhibitor Substances 0.000 title claims description 69
- 229940121372 histone deacetylase inhibitor Drugs 0.000 title claims description 68
- 239000000427 antigen Substances 0.000 claims description 98
- 239000000203 mixture Substances 0.000 claims description 88
- 108091007433 antigens Proteins 0.000 claims description 73
- 102000036639 antigens Human genes 0.000 claims description 73
- 229960005486 vaccine Drugs 0.000 claims description 50
- 239000003814 drug Substances 0.000 claims description 41
- 241000282414 Homo sapiens Species 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 32
- 206010006187 Breast cancer Diseases 0.000 claims description 22
- 208000026310 Breast neoplasm Diseases 0.000 claims description 21
- 108010016918 Histone-Lysine N-Methyltransferase Proteins 0.000 claims description 15
- 239000002532 enzyme inhibitor Substances 0.000 claims description 14
- 239000003968 dna methyltransferase inhibitor Substances 0.000 claims description 9
- 229940022399 cancer vaccine Drugs 0.000 claims description 8
- 102000004127 Cytokines Human genes 0.000 claims description 6
- 108090000695 Cytokines Proteins 0.000 claims description 6
- 201000008275 breast carcinoma Diseases 0.000 claims description 6
- 238000009566 cancer vaccine Methods 0.000 claims description 6
- 230000003750 conditioning effect Effects 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 3
- 230000000415 inactivating effect Effects 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 201000001514 prostate carcinoma Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 206010055008 Gastric sarcoma Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 201000001531 bladder carcinoma Diseases 0.000 claims description 2
- 208000019065 cervical carcinoma Diseases 0.000 claims description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000010749 gastric carcinoma Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000005296 lung carcinoma Diseases 0.000 claims description 2
- 208000025113 myeloid leukemia Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 201000010174 renal carcinoma Diseases 0.000 claims description 2
- 201000000498 stomach carcinoma Diseases 0.000 claims description 2
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 2
- 102000000581 Histone-lysine N-methyltransferase Human genes 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 274
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 132
- 108090000623 proteins and genes Proteins 0.000 description 85
- 229960000604 valproic acid Drugs 0.000 description 66
- 210000004263 induced pluripotent stem cell Anatomy 0.000 description 64
- 230000014509 gene expression Effects 0.000 description 62
- 230000035772 mutation Effects 0.000 description 62
- 210000001671 embryonic stem cell Anatomy 0.000 description 61
- 230000028993 immune response Effects 0.000 description 49
- 238000000034 method Methods 0.000 description 48
- 150000001875 compounds Chemical class 0.000 description 46
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 38
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 36
- 238000011282 treatment Methods 0.000 description 33
- 210000000130 stem cell Anatomy 0.000 description 32
- 241000699670 Mus sp. Species 0.000 description 29
- 239000000126 substance Substances 0.000 description 27
- 230000001965 increasing effect Effects 0.000 description 25
- 210000001778 pluripotent stem cell Anatomy 0.000 description 24
- 108020004414 DNA Proteins 0.000 description 23
- 239000003471 mutagenic agent Substances 0.000 description 22
- 238000002255 vaccination Methods 0.000 description 19
- 230000002163 immunogen Effects 0.000 description 17
- 231100000707 mutagenic chemical Toxicity 0.000 description 17
- 230000003505 mutagenic effect Effects 0.000 description 17
- 102000004169 proteins and genes Human genes 0.000 description 17
- -1 NANOG Proteins 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- 210000000987 immune system Anatomy 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 208000031448 Genomic Instability Diseases 0.000 description 15
- 108700020463 BRCA1 Proteins 0.000 description 14
- 102000036365 BRCA1 Human genes 0.000 description 14
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 14
- 230000004075 alteration Effects 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 102100027770 Histone-lysine N-methyltransferase KMT5B Human genes 0.000 description 13
- 210000001744 T-lymphocyte Anatomy 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 229940125532 enzyme inhibitor Drugs 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 208000011580 syndromic disease Diseases 0.000 description 12
- 239000013598 vector Substances 0.000 description 12
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 11
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 238000012423 maintenance Methods 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 241001529936 Murinae Species 0.000 description 10
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 10
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 10
- 210000000612 antigen-presenting cell Anatomy 0.000 description 10
- 239000013612 plasmid Substances 0.000 description 10
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 10
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 9
- 230000033616 DNA repair Effects 0.000 description 9
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 9
- 101710126211 POU domain, class 5, transcription factor 1 Proteins 0.000 description 9
- 101100247004 Rattus norvegicus Qsox1 gene Proteins 0.000 description 9
- 239000002671 adjuvant Substances 0.000 description 9
- 229940100198 alkylating agent Drugs 0.000 description 9
- 239000002168 alkylating agent Substances 0.000 description 9
- 210000000349 chromosome Anatomy 0.000 description 9
- 230000012010 growth Effects 0.000 description 9
- 231100000350 mutagenesis Toxicity 0.000 description 9
- 230000035755 proliferation Effects 0.000 description 9
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 9
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 9
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 8
- 241000702421 Dependoparvovirus Species 0.000 description 8
- 102100035423 POU domain, class 5, transcription factor 1 Human genes 0.000 description 8
- 206010043276 Teratoma Diseases 0.000 description 8
- 230000005856 abnormality Effects 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 230000006023 anti-tumor response Effects 0.000 description 8
- 229960002756 azacitidine Drugs 0.000 description 8
- 230000002596 correlated effect Effects 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 230000006698 induction Effects 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 210000004072 lung Anatomy 0.000 description 8
- 230000010076 replication Effects 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 238000011285 therapeutic regimen Methods 0.000 description 8
- 231100000277 DNA damage Toxicity 0.000 description 7
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 7
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 7
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 7
- FUSGACRLAFQQRL-UHFFFAOYSA-N N-Ethyl-N-nitrosourea Chemical compound CCN(N=O)C(N)=O FUSGACRLAFQQRL-UHFFFAOYSA-N 0.000 description 7
- 108700019961 Neoplasm Genes Proteins 0.000 description 7
- 102000048850 Neoplasm Genes Human genes 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 7
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 238000002512 chemotherapy Methods 0.000 description 7
- 238000012217 deletion Methods 0.000 description 7
- 230000037430 deletion Effects 0.000 description 7
- 230000001973 epigenetic effect Effects 0.000 description 7
- 238000012239 gene modification Methods 0.000 description 7
- 230000002068 genetic effect Effects 0.000 description 7
- 230000005017 genetic modification Effects 0.000 description 7
- 235000013617 genetically modified food Nutrition 0.000 description 7
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 7
- 210000001082 somatic cell Anatomy 0.000 description 7
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 7
- 238000007482 whole exome sequencing Methods 0.000 description 7
- FKSFKBQGSFSOSM-QFIPXVFZSA-N 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-6-[6-(1-piperazinyl)-3-pyridinyl]-4-indolecarboxamide Chemical group C1=C2N([C@@H](C)CC)C=C(C)C2=C(C(=O)NCC=2C(NC(C)=CC=2C)=O)C=C1C(C=N1)=CC=C1N1CCNCC1 FKSFKBQGSFSOSM-QFIPXVFZSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000005778 DNA damage Effects 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 210000000481 breast Anatomy 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 229940065734 gamma-aminobutyrate Drugs 0.000 description 6
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 6
- 229960001101 ifosfamide Drugs 0.000 description 6
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 6
- 238000009169 immunotherapy Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000007918 intramuscular administration Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 238000002703 mutagenesis Methods 0.000 description 6
- 150000007523 nucleic acids Chemical class 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000007920 subcutaneous administration Methods 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 6
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 5
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 5
- 229940126190 DNA methyltransferase inhibitor Drugs 0.000 description 5
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 5
- 102000003964 Histone deacetylase Human genes 0.000 description 5
- 108090000353 Histone deacetylase Proteins 0.000 description 5
- 108010033040 Histones Proteins 0.000 description 5
- 108010047761 Interferon-alpha Proteins 0.000 description 5
- 102000006992 Interferon-alpha Human genes 0.000 description 5
- 108010065805 Interleukin-12 Proteins 0.000 description 5
- 102000013462 Interleukin-12 Human genes 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- 108091054437 MHC class I family Proteins 0.000 description 5
- 102000043129 MHC class I family Human genes 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 5
- 230000005867 T cell response Effects 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- JJWKPURADFRFRB-UHFFFAOYSA-N carbonyl sulfide Chemical compound O=C=S JJWKPURADFRFRB-UHFFFAOYSA-N 0.000 description 5
- 229940030156 cell vaccine Drugs 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 230000002354 daily effect Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 230000013020 embryo development Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000010362 genome editing Methods 0.000 description 5
- 230000037442 genomic alteration Effects 0.000 description 5
- 238000002744 homologous recombination Methods 0.000 description 5
- 230000006801 homologous recombination Effects 0.000 description 5
- 230000001506 immunosuppresive effect Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 229940117681 interleukin-12 Drugs 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- NSQSAUGJQHDYNO-UHFFFAOYSA-N n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide Chemical group C=1C(C=2C=CC(CN3CCOCC3)=CC=2)=CC(C(=O)NCC=2C(NC(C)=CC=2C)=O)=C(C)C=1N(CC)C1CCOCC1 NSQSAUGJQHDYNO-UHFFFAOYSA-N 0.000 description 5
- 229960003301 nivolumab Drugs 0.000 description 5
- 238000011275 oncology therapy Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 238000011002 quantification Methods 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 238000002626 targeted therapy Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 239000013603 viral vector Substances 0.000 description 5
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 4
- 229940045513 CTLA4 antagonist Drugs 0.000 description 4
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 4
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- 230000007067 DNA methylation Effects 0.000 description 4
- 102100034157 DNA mismatch repair protein Msh2 Human genes 0.000 description 4
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 4
- 108020005004 Guide RNA Proteins 0.000 description 4
- 102100034533 Histone H2AX Human genes 0.000 description 4
- 101001134036 Homo sapiens DNA mismatch repair protein Msh2 Proteins 0.000 description 4
- 101001067891 Homo sapiens Histone H2AX Proteins 0.000 description 4
- 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 description 4
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 4
- 102100040019 Interferon alpha-1/13 Human genes 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 4
- 102000015696 Interleukins Human genes 0.000 description 4
- 108010063738 Interleukins Proteins 0.000 description 4
- 108700021430 Kruppel-Like Factor 4 Proteins 0.000 description 4
- 229910015837 MSH2 Inorganic materials 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 4
- SZMJVTADHFNAIS-BJMVGYQFSA-N chidamide Chemical compound NC1=CC(F)=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)\C=C\C1=CC=CN=C1 SZMJVTADHFNAIS-BJMVGYQFSA-N 0.000 description 4
- 229960004630 chlorambucil Drugs 0.000 description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 4
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 201000011045 hereditary breast ovarian cancer syndrome Diseases 0.000 description 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 230000033607 mismatch repair Effects 0.000 description 4
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 230000003439 radiotherapeutic effect Effects 0.000 description 4
- 230000007115 recruitment Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000008672 reprogramming Effects 0.000 description 4
- 230000028617 response to DNA damage stimulus Effects 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 229960001196 thiotepa Drugs 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 229960000241 vandetanib Drugs 0.000 description 4
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 229960000237 vorinostat Drugs 0.000 description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- ZOIBZSZLMJDVDQ-UHFFFAOYSA-N 1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[4-(4-morpholinylmethyl)phenyl]-4-indazolecarboxamide Chemical group O=C1NC(C)=CC(C)=C1CNC(=O)C1=CC(C=2C=CC(CN3CCOCC3)=CC=2)=CC2=C1C=NN2C1CCCC1 ZOIBZSZLMJDVDQ-UHFFFAOYSA-N 0.000 description 3
- SZAYCVHJDOWSNY-UHFFFAOYSA-N 3-[ethyl(oxan-4-yl)amino]-2-methyl-N-[(1-methyl-3-oxo-5,6,7,8-tetrahydro-2H-isoquinolin-4-yl)methyl]-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]benzamide Chemical group CCN(C1CCOCC1)c1cc(cc(C(=O)NCc2c3CCCCc3c(C)[nH]c2=O)c1C)-c1ccc(nc1)N1CCN(C)CC1 SZAYCVHJDOWSNY-UHFFFAOYSA-N 0.000 description 3
- OMKHWTRUYNAGFG-IEBDPFPHSA-N 3-deazaneplanocin a Chemical group C1=NC=2C(N)=NC=CC=2N1[C@@H]1C=C(CO)[C@@H](O)[C@H]1O OMKHWTRUYNAGFG-IEBDPFPHSA-N 0.000 description 3
- 206010069754 Acquired gene mutation Diseases 0.000 description 3
- 206010000830 Acute leukaemia Diseases 0.000 description 3
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 3
- 108091007743 BRCA1/2 Proteins 0.000 description 3
- 101150008921 Brca2 gene Proteins 0.000 description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 3
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 3
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- 108010077544 Chromatin Proteins 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 230000004543 DNA replication Effects 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 description 3
- 108010074604 Epoetin Alfa Proteins 0.000 description 3
- 102000003951 Erythropoietin Human genes 0.000 description 3
- 108090000394 Erythropoietin Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108091029865 Exogenous DNA Proteins 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- ULNXAWLQFZMIHX-UHFFFAOYSA-N GSK343 Chemical group C1=C(C)NC(=O)C(CNC(=O)C=2C=3C=NN(C=3C=C(C=2)C=2C=C(N=CC=2)N2CCN(C)CC2)C(C)C)=C1CCC ULNXAWLQFZMIHX-UHFFFAOYSA-N 0.000 description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 3
- 208000008051 Hereditary Nonpolyposis Colorectal Neoplasms Diseases 0.000 description 3
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 3
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 3
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 3
- 102000004388 Interleukin-4 Human genes 0.000 description 3
- 108090000978 Interleukin-4 Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- 201000005027 Lynch syndrome Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 3
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 3
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 3
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 3
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 3
- 108700012920 TNF Proteins 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 3
- 150000008052 alkyl sulfonates Chemical class 0.000 description 3
- 229960000473 altretamine Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 238000003491 array Methods 0.000 description 3
- 230000033590 base-excision repair Effects 0.000 description 3
- 210000002459 blastocyst Anatomy 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229960002092 busulfan Drugs 0.000 description 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 3
- 229930195731 calicheamicin Natural products 0.000 description 3
- 229960005243 carmustine Drugs 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000013043 chemical agent Substances 0.000 description 3
- 229950009221 chidamide Drugs 0.000 description 3
- 210000003483 chromatin Anatomy 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 229960003901 dacarbazine Drugs 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 description 3
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 3
- 229940105423 erythropoietin Drugs 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 229960004783 fotemustine Drugs 0.000 description 3
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 3
- 229960002411 imatinib Drugs 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 229960001438 immunostimulant agent Drugs 0.000 description 3
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 3
- 229950008097 improsulfan Drugs 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 230000010354 integration Effects 0.000 description 3
- 229940028885 interleukin-4 Drugs 0.000 description 3
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 3
- 101150111214 lin-28 gene Proteins 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 229960002247 lomustine Drugs 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 210000001161 mammalian embryo Anatomy 0.000 description 3
- 229960004961 mechlorethamine Drugs 0.000 description 3
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 3
- 229960001924 melphalan Drugs 0.000 description 3
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 3
- 229950010913 mitolactol Drugs 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 231100000219 mutagenic Toxicity 0.000 description 3
- 230000000869 mutational effect Effects 0.000 description 3
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 3
- IFSQHIRDVVFJSQ-UHFFFAOYSA-N n-[(1,6-dimethyl-2-oxo-4-propylpyridin-3-yl)methyl]-n-methyl-1-propan-2-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)pyridin-3-yl]indazole-4-carboxamide Chemical group C1=C(C)N(C)C(=O)C(CN(C)C(=O)C=2C=3C=NN(C=3C=C(C=2)C=2C=NC(=CC=2)N2CCN(CC2)C(C)C)C(C)C)=C1CCC IFSQHIRDVVFJSQ-UHFFFAOYSA-N 0.000 description 3
- DPJNKUOXBZSZAI-UHFFFAOYSA-N n-[(6-methyl-2-oxo-4-propyl-1h-pyridin-3-yl)methyl]-1-propan-2-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)pyridin-3-yl]indazole-4-carboxamide Chemical group C1=C(C)NC(=O)C(CNC(=O)C=2C=3C=NN(C=3C=C(C=2)C=2C=NC(=CC=2)N2CCN(CC2)C(C)C)C(C)C)=C1CCC DPJNKUOXBZSZAI-UHFFFAOYSA-N 0.000 description 3
- 229960001420 nimustine Drugs 0.000 description 3
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 3
- 230000020520 nucleotide-excision repair Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000013600 plasmid vector Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 3
- 229960004694 prednimustine Drugs 0.000 description 3
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 3
- 229960000624 procarbazine Drugs 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 229960002185 ranimustine Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000037439 somatic mutation Effects 0.000 description 3
- 229960001052 streptozocin Drugs 0.000 description 3
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 229960000875 trofosfamide Drugs 0.000 description 3
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 241001430294 unidentified retrovirus Species 0.000 description 3
- PSVUJBVBCOISSP-SPFKKGSWSA-N (2s,3r,4s,5s,6r)-2-bis(2-chloroethylamino)phosphoryloxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1O[C@@H](OP(=O)(NCCCl)NCCCl)[C@H](O)[C@@H](O)[C@@H]1O PSVUJBVBCOISSP-SPFKKGSWSA-N 0.000 description 2
- PVCULFYROUOVGJ-UHFFFAOYSA-N 1-[2-chloroethyl(methylsulfonyl)amino]-3-methyl-1-methylsulfonylurea Chemical compound CNC(=O)N(S(C)(=O)=O)N(S(C)(=O)=O)CCCl PVCULFYROUOVGJ-UHFFFAOYSA-N 0.000 description 2
- MAUCONCHVWBMHK-UHFFFAOYSA-N 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide Chemical compound O1C2=CC=CC=C2C(CN(C)C)=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 MAUCONCHVWBMHK-UHFFFAOYSA-N 0.000 description 2
- PRDJGNVQBVXXEO-UHFFFAOYSA-N 3-cyanopropyl carbamimidothioate Chemical compound NC(=N)SCCCC#N PRDJGNVQBVXXEO-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- 241001655883 Adeno-associated virus - 1 Species 0.000 description 2
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- MXPOCMVWFLDDLZ-NSCUHMNNSA-N Apaziquone Chemical compound CN1C(\C=C\CO)=C(CO)C(C2=O)=C1C(=O)C=C2N1CC1 MXPOCMVWFLDDLZ-NSCUHMNNSA-N 0.000 description 2
- 108090000461 Aurora Kinase A Proteins 0.000 description 2
- 102000004000 Aurora Kinase A Human genes 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 101150072950 BRCA1 gene Proteins 0.000 description 2
- 108700020462 BRCA2 Proteins 0.000 description 2
- 102000052609 BRCA2 Human genes 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 102100035631 Bloom syndrome protein Human genes 0.000 description 2
- 108091009167 Bloom syndrome protein Proteins 0.000 description 2
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 2
- 102100036170 C-X-C motif chemokine 9 Human genes 0.000 description 2
- 102100038078 CD276 antigen Human genes 0.000 description 2
- 102100025805 Cadherin-1 Human genes 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- 108091007854 Cdh1/Fizzy-related Proteins 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 206010065163 Clonal evolution Diseases 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 2
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 2
- 102100038111 Cyclin-dependent kinase 12 Human genes 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 102100021147 DNA mismatch repair protein Msh6 Human genes 0.000 description 2
- 102100037799 DNA-binding protein Ikaros Human genes 0.000 description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 2
- 201000006107 Familial adenomatous polyposis Diseases 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
- 206010051922 Hereditary non-polyposis colorectal cancer syndrome Diseases 0.000 description 2
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 description 2
- 102100037164 Histone-lysine N-methyltransferase EZH1 Human genes 0.000 description 2
- 108050001949 Histone-lysine N-methyltransferase EZH1 Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 2
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 2
- 101000947172 Homo sapiens C-X-C motif chemokine 9 Proteins 0.000 description 2
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 2
- 101000884345 Homo sapiens Cyclin-dependent kinase 12 Proteins 0.000 description 2
- 101000968658 Homo sapiens DNA mismatch repair protein Msh6 Proteins 0.000 description 2
- 101000599038 Homo sapiens DNA-binding protein Ikaros Proteins 0.000 description 2
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 description 2
- 101000599886 Homo sapiens Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 description 2
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 2
- 101000602930 Homo sapiens Nuclear receptor coactivator 2 Proteins 0.000 description 2
- 101000798015 Homo sapiens RAC-beta serine/threonine-protein kinase Proteins 0.000 description 2
- 101000687737 Homo sapiens SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 Proteins 0.000 description 2
- 101000783404 Homo sapiens Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Proteins 0.000 description 2
- 101000666775 Homo sapiens T-box transcription factor TBX3 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 2
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 2
- 102100026720 Interferon beta Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 2
- 241000713666 Lentivirus Species 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- 102000016397 Methyltransferase Human genes 0.000 description 2
- 108060004795 Methyltransferase Proteins 0.000 description 2
- 108700011259 MicroRNAs Proteins 0.000 description 2
- 108010074346 Mismatch Repair Endonuclease PMS2 Proteins 0.000 description 2
- 102100037480 Mismatch repair endonuclease PMS2 Human genes 0.000 description 2
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 2
- 206010068052 Mosaicism Diseases 0.000 description 2
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 2
- 102000013609 MutL Protein Homolog 1 Human genes 0.000 description 2
- 108010026664 MutL Protein Homolog 1 Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 2
- PAWIYAYFNXQGAP-UHFFFAOYSA-N N-hydroxy-2-[4-[[(1-methyl-3-indolyl)methylamino]methyl]-1-piperidinyl]-5-pyrimidinecarboxamide Chemical compound C12=CC=CC=C2N(C)C=C1CNCC(CC1)CCN1C1=NC=C(C(=O)NO)C=N1 PAWIYAYFNXQGAP-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- ARFHIAQFJWUCFH-IZZDOVSWSA-N Nifurtimox Chemical compound CC1CS(=O)(=O)CCN1\N=C\C1=CC=C([N+]([O-])=O)O1 ARFHIAQFJWUCFH-IZZDOVSWSA-N 0.000 description 2
- 102100037226 Nuclear receptor coactivator 2 Human genes 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102100032315 RAC-beta serine/threonine-protein kinase Human genes 0.000 description 2
- 238000003559 RNA-seq method Methods 0.000 description 2
- 108010068097 Rad51 Recombinase Proteins 0.000 description 2
- 102000002490 Rad51 Recombinase Human genes 0.000 description 2
- 108010055623 S-Phase Kinase-Associated Proteins Proteins 0.000 description 2
- 102100034374 S-phase kinase-associated protein 2 Human genes 0.000 description 2
- 102100024777 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 Human genes 0.000 description 2
- 102100036122 Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Human genes 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 230000024932 T cell mediated immunity Effects 0.000 description 2
- 102100038409 T-box transcription factor TBX3 Human genes 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- YCPOZVAOBBQLRI-WDSKDSINSA-N Treosulfan Chemical compound CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O YCPOZVAOBBQLRI-WDSKDSINSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical group [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 2
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052767 actinium Inorganic materials 0.000 description 2
- QQINRWTZWGJFDB-UHFFFAOYSA-N actinium atom Chemical compound [Ac] QQINRWTZWGJFDB-UHFFFAOYSA-N 0.000 description 2
- 229940125666 actinium-225 Drugs 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 229960001570 ademetionine Drugs 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 2
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 2
- 229940037003 alum Drugs 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 2
- 230000005975 antitumor immune response Effects 0.000 description 2
- 229950002465 apaziquone Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 2
- 229960003094 belinostat Drugs 0.000 description 2
- 229960002707 bendamustine Drugs 0.000 description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 2
- 238000007622 bioinformatic analysis Methods 0.000 description 2
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 101150038500 cas9 gene Proteins 0.000 description 2
- 230000007969 cellular immunity Effects 0.000 description 2
- 239000002962 chemical mutagen Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 2
- 229960002424 collagenase Drugs 0.000 description 2
- 229940047120 colony stimulating factors Drugs 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 229960003603 decitabine Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000002074 deregulated effect Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 230000005782 double-strand break Effects 0.000 description 2
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 210000002308 embryonic cell Anatomy 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229950005837 entinostat Drugs 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 229960004750 estramustine phosphate Drugs 0.000 description 2
- ADFOJJHRTBFFOF-RBRWEJTLSA-N estramustine phosphate Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 ADFOJJHRTBFFOF-RBRWEJTLSA-N 0.000 description 2
- YQZNKYXGZSVEHI-VXKWHMMOSA-N ethyl (2s)-2-[[(2s)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-3-(4-fluorophenyl)propanoate Chemical compound C([C@@H](C(=O)OCC)NC(=O)[C@@H](N)CC=1C=CC(=CC=1)N(CCCl)CCCl)C1=CC=C(F)C=C1 YQZNKYXGZSVEHI-VXKWHMMOSA-N 0.000 description 2
- 210000001808 exosome Anatomy 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000037433 frameshift Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 229950011595 glufosfamide Drugs 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 230000006058 immune tolerance Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 229940047122 interleukins Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000002361 inverse photoelectron spectroscopy Methods 0.000 description 2
- 230000005865 ionizing radiation Effects 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 229950000340 laromustine Drugs 0.000 description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 229950000680 lurbinectedin Drugs 0.000 description 2
- YDDMIZRDDREKEP-HWTBNCOESA-N lurbinectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1NC1=CC=C(C=C13)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 YDDMIZRDDREKEP-HWTBNCOESA-N 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 210000005075 mammary gland Anatomy 0.000 description 2
- 229950009924 melphalan flufenamide Drugs 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 238000010197 meta-analysis Methods 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 229960005485 mitobronitol Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 229950007812 mocetinostat Drugs 0.000 description 2
- 239000002539 nanocarrier Substances 0.000 description 2
- 229950007221 nedaplatin Drugs 0.000 description 2
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 2
- 229960002644 nifurtimox Drugs 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 229960005184 panobinostat Drugs 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 229960002621 pembrolizumab Drugs 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- JHDKZFFAIZKUCU-ZRDIBKRKSA-N pracinostat Chemical compound ONC(=O)/C=C/C1=CC=C2N(CCN(CC)CC)C(CCCC)=NC2=C1 JHDKZFFAIZKUCU-ZRDIBKRKSA-N 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011435 rock Substances 0.000 description 2
- 229960003452 romidepsin Drugs 0.000 description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 2
- 108010091666 romidepsin Proteins 0.000 description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 2
- 108010038379 sargramostim Proteins 0.000 description 2
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- UYCAUPASBSROMS-UHFFFAOYSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)F UYCAUPASBSROMS-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000000392 somatic effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229950004774 tazemetostat Drugs 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 2
- 229960000977 trabectedin Drugs 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 229960003181 treosulfan Drugs 0.000 description 2
- 150000003918 triazines Chemical class 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 102000003390 tumor necrosis factor Human genes 0.000 description 2
- BNJNAEJASPUJTO-DUOHOMBCSA-N vadastuximab talirine Chemical compound COc1ccc(cc1)C2=CN3[C@@H](C2)C=Nc4cc(OCCCOc5cc6N=C[C@@H]7CC(=CN7C(=O)c6cc5OC)c8ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCCCCN9C(=O)C[C@@H](SC[C@H](N)C(=O)O)C9=O)C(C)C)cc8)c(OC)cc4C3=O BNJNAEJASPUJTO-DUOHOMBCSA-N 0.000 description 2
- 229950000578 vatalanib Drugs 0.000 description 2
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 2
- 238000012070 whole genome sequencing analysis Methods 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- WCWUXEGQKLTGDX-LLVKDONJSA-N (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](O)C)=C1 WCWUXEGQKLTGDX-LLVKDONJSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 1
- KCOYQXZDFIIGCY-CZIZESTLSA-N (3e)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(N\C(N2)=C/3C(=C4C(F)=CC=CC4=NC\3=O)N)C2=C1 KCOYQXZDFIIGCY-CZIZESTLSA-N 0.000 description 1
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- AESVUZLWRXEGEX-DKCAWCKPSA-N (7S,9R)-7-[(2S,4R,5R,6R)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione iron(3+) Chemical compound [Fe+3].COc1cccc2C(=O)c3c(O)c4C[C@@](O)(C[C@H](O[C@@H]5C[C@@H](N)[C@@H](O)[C@@H](C)O5)c4c(O)c3C(=O)c12)C(=O)CO AESVUZLWRXEGEX-DKCAWCKPSA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- RCFNNLSZHVHCEK-IMHLAKCZSA-N (7s,9s)-7-(4-amino-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)C1CC([NH3+])CC(C)O1 RCFNNLSZHVHCEK-IMHLAKCZSA-N 0.000 description 1
- NOPNWHSMQOXAEI-PUCKCBAPSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-(2,3-dihydropyrrol-1-yl)-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCC=C1 NOPNWHSMQOXAEI-PUCKCBAPSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- PJOHVEQSYPOERL-SHEAVXILSA-N (e)-n-[(4r,4as,7ar,12br)-3-(cyclopropylmethyl)-9-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a-yl]-3-(4-methylphenyl)prop-2-enamide Chemical compound C1=CC(C)=CC=C1\C=C\C(=O)N[C@]1(CCC(=O)[C@@H]2O3)[C@H]4CC5=CC=C(O)C3=C5[C@]12CCN4CC1CC1 PJOHVEQSYPOERL-SHEAVXILSA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- VPBYZLCHOKSGRX-UHFFFAOYSA-N 1-[2-chloro-4-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-propylurea Chemical compound C1=C(Cl)C(NC(=O)NCCC)=CC=C1OC1=NC=NC2=CC(OC)=C(OC)C=C12 VPBYZLCHOKSGRX-UHFFFAOYSA-N 0.000 description 1
- SPMVMDHWKHCIDT-UHFFFAOYSA-N 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 1
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 1
- 102100025425 2-oxoglutarate and iron-dependent oxygenase JMJD4 Human genes 0.000 description 1
- ZZUZYEMRHCMVTB-UHFFFAOYSA-N 2-phenylethynesulfonamide Chemical compound NS(=O)(=O)C#CC1=CC=CC=C1 ZZUZYEMRHCMVTB-UHFFFAOYSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-QLKYHASDSA-N 3'-deamino-3'-(3-cyanomorpholin-4-yl)doxorubicin Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-QLKYHASDSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AXRCEOKUDYDWLF-UHFFFAOYSA-N 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1=CC=CC=N1 AXRCEOKUDYDWLF-UHFFFAOYSA-N 0.000 description 1
- FGTCROZDHDSNIO-UHFFFAOYSA-N 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)C1=C(NCC=2C3=CC=CC=C3N=CC=2)C=CS1 FGTCROZDHDSNIO-UHFFFAOYSA-N 0.000 description 1
- HXHAJRMTJXHJJZ-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 HXHAJRMTJXHJJZ-UHFFFAOYSA-N 0.000 description 1
- 102100034488 39S ribosomal protein S18a, mitochondrial Human genes 0.000 description 1
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 1
- QFCXANHHBCGMAS-UHFFFAOYSA-N 4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxymethyl]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(COC=2C=3OC=CC=3C(NC=3C=CC(Cl)=CC=3)=NN=2)=C1 QFCXANHHBCGMAS-UHFFFAOYSA-N 0.000 description 1
- HHFBDROWDBDFBR-UHFFFAOYSA-N 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC1=NC=C(CN=C(C=2C3=CC=C(Cl)C=2)C=2C(=CC=CC=2F)F)C3=N1 HHFBDROWDBDFBR-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- 101150060295 58 gene Proteins 0.000 description 1
- OSXFATOLZGZLSK-UHFFFAOYSA-N 6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-[1-(phenylmethyl)-4-piperidinyl]-4-quinazolinamine Chemical compound C=12C=C(OC)C(OC)=CC2=NC(N2CCN(C)CCC2)=NC=1NC(CC1)CCN1CC1=CC=CC=C1 OSXFATOLZGZLSK-UHFFFAOYSA-N 0.000 description 1
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 1
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 description 1
- YCWQAMGASJSUIP-YFKPBYRVSA-N 6-diazo-5-oxo-L-norleucine Chemical compound OC(=O)[C@@H](N)CCC(=O)C=[N+]=[N-] YCWQAMGASJSUIP-YFKPBYRVSA-N 0.000 description 1
- UFGQWTWQNIGAEB-UHFFFAOYSA-N 7-chloroquinoline-3-carboxylic acid Chemical compound C1=C(Cl)C=CC2=CC(C(=O)O)=CN=C21 UFGQWTWQNIGAEB-UHFFFAOYSA-N 0.000 description 1
- DBQULWBPIZECMN-UHFFFAOYSA-N 8,16,26,34,36-pentahydroxyhentetracontane-2,6,10,14,18,24,28,32-octone Chemical compound CCCCCC(O)CC(O)CC(=O)CCCC(=O)CC(O)CC(=O)CCCCCC(=O)CC(O)CC(=O)CCCC(=O)CC(O)CC(=O)CCCC(C)=O DBQULWBPIZECMN-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 102100026007 ADAM DEC1 Human genes 0.000 description 1
- 108091005560 ADGRG3 Proteins 0.000 description 1
- OONFNUWBHFSNBT-HXUWFJFHSA-N AEE788 Chemical compound C1CN(CC)CCN1CC1=CC=C(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)C=C1 OONFNUWBHFSNBT-HXUWFJFHSA-N 0.000 description 1
- 108700001666 APC Genes Proteins 0.000 description 1
- 102100034402 ATP-dependent RNA helicase DDX39A Human genes 0.000 description 1
- 102100040037 Adhesion G protein-coupled receptor G3 Human genes 0.000 description 1
- 102100031090 Alpha-catulin Human genes 0.000 description 1
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 102100021979 Asporin Human genes 0.000 description 1
- 206010003594 Ataxia telangiectasia Diseases 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 108700040618 BRCA1 Genes Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 208000005692 Bloom Syndrome Diseases 0.000 description 1
- 102100025423 Bone morphogenetic protein receptor type-1A Human genes 0.000 description 1
- 102100031746 Bone sialoprotein 2 Human genes 0.000 description 1
- 102100022046 Brain-specific serine protease 4 Human genes 0.000 description 1
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 1
- KGGVWMAPBXIMEM-ZRTAFWODSA-N Bullatacinone Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@H]2OC(=O)[C@H](CC(C)=O)C2)CC1 KGGVWMAPBXIMEM-ZRTAFWODSA-N 0.000 description 1
- KGGVWMAPBXIMEM-JQFCFGFHSA-N Bullatacinone Natural products O=C(C[C@H]1C(=O)O[C@H](CCCCCCCCCC[C@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)C1)C KGGVWMAPBXIMEM-JQFCFGFHSA-N 0.000 description 1
- 102100036849 C-C motif chemokine 24 Human genes 0.000 description 1
- 101710185679 CD276 antigen Proteins 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 108700020472 CDC20 Proteins 0.000 description 1
- LLVZBTWPGQVVLW-SNAWJCMRSA-N CP-724714 Chemical compound C12=CC(/C=C/CNC(=O)COC)=CC=C2N=CN=C1NC(C=C1C)=CC=C1OC1=CC=C(C)N=C1 LLVZBTWPGQVVLW-SNAWJCMRSA-N 0.000 description 1
- 102100040755 CREB-regulated transcription coactivator 3 Human genes 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- 102100024153 Cadherin-15 Human genes 0.000 description 1
- 239000005461 Canertinib Substances 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 101150023302 Cdc20 gene Proteins 0.000 description 1
- 102100038099 Cell division cycle protein 20 homolog Human genes 0.000 description 1
- 102100034231 Cell surface A33 antigen Human genes 0.000 description 1
- 102100023126 Cell surface glycoprotein MUC18 Human genes 0.000 description 1
- 102000011682 Centromere Protein A Human genes 0.000 description 1
- 108010076303 Centromere Protein A Proteins 0.000 description 1
- 102100023344 Centromere protein F Human genes 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- XCDXSSFOJZZGQC-UHFFFAOYSA-N Chlornaphazine Chemical compound C1=CC=CC2=CC(N(CCCl)CCCl)=CC=C21 XCDXSSFOJZZGQC-UHFFFAOYSA-N 0.000 description 1
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 102100038447 Claudin-4 Human genes 0.000 description 1
- 208000010200 Cockayne syndrome Diseases 0.000 description 1
- 102100032952 Condensin complex subunit 3 Human genes 0.000 description 1
- 206010053138 Congenital aplastic anaemia Diseases 0.000 description 1
- 101150073133 Cpt1a gene Proteins 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 102100035429 Cystathionine gamma-lyase Human genes 0.000 description 1
- 102100031621 Cysteine and glycine-rich protein 2 Human genes 0.000 description 1
- 102100032756 Cysteine-rich protein 1 Human genes 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 102100038497 Cytokine receptor-like factor 2 Human genes 0.000 description 1
- 102100037165 DBH-like monooxygenase protein 1 Human genes 0.000 description 1
- 102000007528 DNA Polymerase III Human genes 0.000 description 1
- 108010071146 DNA Polymerase III Proteins 0.000 description 1
- 108010041986 DNA Vaccines Proteins 0.000 description 1
- 230000007035 DNA breakage Effects 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 230000035131 DNA demethylation Effects 0.000 description 1
- 208000027816 DNA repair disease Diseases 0.000 description 1
- 102100039606 DNA replication licensing factor MCM3 Human genes 0.000 description 1
- 102100033711 DNA replication licensing factor MCM7 Human genes 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 101100239628 Danio rerio myca gene Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 102100024354 Dedicator of cytokinesis protein 6 Human genes 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- 101001046554 Dictyostelium discoideum Thymidine kinase 1 Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 102100024364 Disintegrin and metalloproteinase domain-containing protein 8 Human genes 0.000 description 1
- 102100037980 Disks large-associated protein 5 Human genes 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229930193152 Dynemicin Natural products 0.000 description 1
- 102000012804 EPCAM Human genes 0.000 description 1
- 101150084967 EPCAM gene Proteins 0.000 description 1
- 102100039577 ETS translocation variant 5 Human genes 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- AFMYMMXSQGUCBK-UHFFFAOYSA-N Endynamicin A Natural products C1#CC=CC#CC2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3C34OC32C(C)C(C(O)=O)=C(OC)C41 AFMYMMXSQGUCBK-UHFFFAOYSA-N 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010055323 EphB4 Receptor Proteins 0.000 description 1
- 102100031983 Ephrin type-B receptor 4 Human genes 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 1
- 229930189413 Esperamicin Natural products 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 102100029055 Exostosin-1 Human genes 0.000 description 1
- 102100036936 Extended synaptotagmin-3 Human genes 0.000 description 1
- 108010067741 Fanconi Anemia Complementation Group N protein Proteins 0.000 description 1
- 201000004939 Fanconi anemia Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 101001067614 Flaveria pringlei Serine hydroxymethyltransferase 2, mitochondrial Proteins 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 210000000712 G cell Anatomy 0.000 description 1
- 102100032340 G2/mitotic-specific cyclin-B1 Human genes 0.000 description 1
- 102100033201 G2/mitotic-specific cyclin-B2 Human genes 0.000 description 1
- 108010062427 GDP-mannose 4,6-dehydratase Proteins 0.000 description 1
- 102000002312 GDPmannose 4,6-dehydratase Human genes 0.000 description 1
- 102000053334 GRB10 Adaptor Human genes 0.000 description 1
- 108700031835 GRB10 Adaptor Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 230000010558 Gene Alterations Effects 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 101150090959 Grb10 gene Proteins 0.000 description 1
- 241000713858 Harvey murine sarcoma virus Species 0.000 description 1
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 208000017095 Hereditary nonpolyposis colon cancer Diseases 0.000 description 1
- 102100022128 High mobility group protein B2 Human genes 0.000 description 1
- 102100033636 Histone H3.2 Human genes 0.000 description 1
- 229940122825 Histone methyltransferase inhibitor Drugs 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 101000934666 Homo sapiens 2-oxoglutarate and iron-dependent oxygenase JMJD4 Proteins 0.000 description 1
- 101000639842 Homo sapiens 39S ribosomal protein S18a, mitochondrial Proteins 0.000 description 1
- 101000719904 Homo sapiens ADAM DEC1 Proteins 0.000 description 1
- 101000923749 Homo sapiens ATP-dependent RNA helicase DDX39A Proteins 0.000 description 1
- 101000922043 Homo sapiens Alpha-catulin Proteins 0.000 description 1
- 101000752724 Homo sapiens Asporin Proteins 0.000 description 1
- 101000934638 Homo sapiens Bone morphogenetic protein receptor type-1A Proteins 0.000 description 1
- 101000707248 Homo sapiens Bone sialoprotein 2 Proteins 0.000 description 1
- 101000896891 Homo sapiens Brain-specific serine protease 4 Proteins 0.000 description 1
- 101000713078 Homo sapiens C-C motif chemokine 24 Proteins 0.000 description 1
- 101000945426 Homo sapiens CB1 cannabinoid receptor-interacting protein 1 Proteins 0.000 description 1
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000891906 Homo sapiens CREB-regulated transcription coactivator 3 Proteins 0.000 description 1
- 101000762242 Homo sapiens Cadherin-15 Proteins 0.000 description 1
- 101000714553 Homo sapiens Cadherin-3 Proteins 0.000 description 1
- 101000996823 Homo sapiens Cell surface A33 antigen Proteins 0.000 description 1
- 101000623903 Homo sapiens Cell surface glycoprotein MUC18 Proteins 0.000 description 1
- 101000907941 Homo sapiens Centromere protein F Proteins 0.000 description 1
- 101000882890 Homo sapiens Claudin-4 Proteins 0.000 description 1
- 101000942622 Homo sapiens Condensin complex subunit 3 Proteins 0.000 description 1
- 101000737584 Homo sapiens Cystathionine gamma-lyase Proteins 0.000 description 1
- 101000940752 Homo sapiens Cysteine and glycine-rich protein 2 Proteins 0.000 description 1
- 101000942084 Homo sapiens Cysteine-rich protein 1 Proteins 0.000 description 1
- 101000956427 Homo sapiens Cytokine receptor-like factor 2 Proteins 0.000 description 1
- 101001028766 Homo sapiens DBH-like monooxygenase protein 1 Proteins 0.000 description 1
- 101000963174 Homo sapiens DNA replication licensing factor MCM3 Proteins 0.000 description 1
- 101001018431 Homo sapiens DNA replication licensing factor MCM7 Proteins 0.000 description 1
- 101001052950 Homo sapiens Dedicator of cytokinesis protein 6 Proteins 0.000 description 1
- 101000929429 Homo sapiens Discoidin domain-containing receptor 2 Proteins 0.000 description 1
- 101000832767 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 8 Proteins 0.000 description 1
- 101000951365 Homo sapiens Disks large-associated protein 5 Proteins 0.000 description 1
- 101001095815 Homo sapiens E3 ubiquitin-protein ligase RING2 Proteins 0.000 description 1
- 101000813745 Homo sapiens ETS translocation variant 5 Proteins 0.000 description 1
- 101000918311 Homo sapiens Exostosin-1 Proteins 0.000 description 1
- 101000851512 Homo sapiens Extended synaptotagmin-3 Proteins 0.000 description 1
- 101000868643 Homo sapiens G2/mitotic-specific cyclin-B1 Proteins 0.000 description 1
- 101000713023 Homo sapiens G2/mitotic-specific cyclin-B2 Proteins 0.000 description 1
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 1
- 101001045791 Homo sapiens High mobility group protein B2 Proteins 0.000 description 1
- 101000867103 Homo sapiens Hormonally up-regulated neu tumor-associated kinase Proteins 0.000 description 1
- 101000988651 Homo sapiens Humanin-like 1 Proteins 0.000 description 1
- 101001081176 Homo sapiens Hyaluronan mediated motility receptor Proteins 0.000 description 1
- 101001050472 Homo sapiens Integral membrane protein 2A Proteins 0.000 description 1
- 101001037246 Homo sapiens Interleukin-27 receptor subunit alpha Proteins 0.000 description 1
- 101001050286 Homo sapiens Jupiter microtubule associated homolog 1 Proteins 0.000 description 1
- 101001046976 Homo sapiens KN motif and ankyrin repeat domain-containing protein 3 Proteins 0.000 description 1
- 101001007027 Homo sapiens Keratin, type II cuticular Hb1 Proteins 0.000 description 1
- 101001027621 Homo sapiens Kinesin-like protein KIF20A Proteins 0.000 description 1
- 101000605743 Homo sapiens Kinesin-like protein KIF23 Proteins 0.000 description 1
- 101001050567 Homo sapiens Kinesin-like protein KIF2C Proteins 0.000 description 1
- 101000697493 Homo sapiens Large proline-rich protein BAG6 Proteins 0.000 description 1
- 101001038435 Homo sapiens Leucine-zipper-like transcriptional regulator 1 Proteins 0.000 description 1
- 101001018100 Homo sapiens Lysozyme C Proteins 0.000 description 1
- 101001014572 Homo sapiens MARCKS-related protein Proteins 0.000 description 1
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 description 1
- 101001057193 Homo sapiens Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Proteins 0.000 description 1
- 101000954986 Homo sapiens Merlin Proteins 0.000 description 1
- 101000629400 Homo sapiens Mesoderm-specific transcript homolog protein Proteins 0.000 description 1
- 101000653360 Homo sapiens Methylcytosine dioxygenase TET1 Proteins 0.000 description 1
- 101000929583 Homo sapiens N(G),N(G)-dimethylarginine dimethylaminohydrolase 2 Proteins 0.000 description 1
- 101000588230 Homo sapiens N-alpha-acetyltransferase 10 Proteins 0.000 description 1
- 101001112714 Homo sapiens NAD kinase Proteins 0.000 description 1
- 101100241084 Homo sapiens NRTN gene Proteins 0.000 description 1
- 101000583239 Homo sapiens Nicotinate-nucleotide pyrophosphorylase [carboxylating] Proteins 0.000 description 1
- 101000601047 Homo sapiens Nidogen-1 Proteins 0.000 description 1
- 101000991410 Homo sapiens Nucleolar and spindle-associated protein 1 Proteins 0.000 description 1
- 101000986810 Homo sapiens P2Y purinoceptor 8 Proteins 0.000 description 1
- 101000738901 Homo sapiens PMS1 protein homolog 1 Proteins 0.000 description 1
- 101001120056 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit alpha Proteins 0.000 description 1
- 101001116302 Homo sapiens Platelet endothelial cell adhesion molecule Proteins 0.000 description 1
- 101000583702 Homo sapiens Pleckstrin homology-like domain family A member 2 Proteins 0.000 description 1
- 101000728236 Homo sapiens Polycomb group protein ASXL1 Proteins 0.000 description 1
- 101000584499 Homo sapiens Polycomb protein SUZ12 Proteins 0.000 description 1
- 101001054596 Homo sapiens Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial Proteins 0.000 description 1
- 101000973947 Homo sapiens Probable 28S rRNA (cytosine(4447)-C(5))-methyltransferase Proteins 0.000 description 1
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 description 1
- 101000945496 Homo sapiens Proliferation marker protein Ki-67 Proteins 0.000 description 1
- 101001080624 Homo sapiens Proline/serine-rich coiled-coil protein 1 Proteins 0.000 description 1
- 101000611053 Homo sapiens Proteasome subunit beta type-2 Proteins 0.000 description 1
- 101000739214 Homo sapiens Protein SGT1 homolog Proteins 0.000 description 1
- 101000789800 Homo sapiens Protein YIPF3 Proteins 0.000 description 1
- 101001000998 Homo sapiens Protein phosphatase 1 regulatory subunit 12C Proteins 0.000 description 1
- 101000687060 Homo sapiens Protein phosphatase 1 regulatory subunit 1A Proteins 0.000 description 1
- 101000617017 Homo sapiens Protein scribble homolog Proteins 0.000 description 1
- 101000702384 Homo sapiens Protein sprouty homolog 2 Proteins 0.000 description 1
- 101000629617 Homo sapiens Protein sprouty homolog 4 Proteins 0.000 description 1
- 101001099586 Homo sapiens Pyridoxal kinase Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101001078093 Homo sapiens Reticulocalbin-1 Proteins 0.000 description 1
- 101001106309 Homo sapiens Rho GTPase-activating protein 8 Proteins 0.000 description 1
- 101000575639 Homo sapiens Ribonucleoside-diphosphate reductase subunit M2 Proteins 0.000 description 1
- 101000598783 Homo sapiens SCRIB overlapping open reading frame protein Proteins 0.000 description 1
- 101001093937 Homo sapiens SEC14-like protein 1 Proteins 0.000 description 1
- 101000709055 Homo sapiens SLAIN motif-containing protein 1 Proteins 0.000 description 1
- 101000633782 Homo sapiens SLAM family member 8 Proteins 0.000 description 1
- 101000864743 Homo sapiens Secreted frizzled-related protein 1 Proteins 0.000 description 1
- 101000587820 Homo sapiens Selenide, water dikinase 1 Proteins 0.000 description 1
- 101001067604 Homo sapiens Serine hydroxymethyltransferase, mitochondrial Proteins 0.000 description 1
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 1
- 101000911601 Homo sapiens Soluble lamin-associated protein of 75 kDa Proteins 0.000 description 1
- 101000618133 Homo sapiens Sperm-associated antigen 5 Proteins 0.000 description 1
- 101000616172 Homo sapiens Splicing factor 3B subunit 3 Proteins 0.000 description 1
- 101000661807 Homo sapiens Suppressor of tumorigenicity 14 protein Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 101000830894 Homo sapiens Targeting protein for Xklp2 Proteins 0.000 description 1
- 101000845170 Homo sapiens Thymic stromal lymphopoietin Proteins 0.000 description 1
- 101000945477 Homo sapiens Thymidine kinase, cytosolic Proteins 0.000 description 1
- 101000834937 Homo sapiens Tomoregulin-1 Proteins 0.000 description 1
- 101000838086 Homo sapiens Transaldolase Proteins 0.000 description 1
- 101000687905 Homo sapiens Transcription factor SOX-2 Proteins 0.000 description 1
- 101000800463 Homo sapiens Transketolase Proteins 0.000 description 1
- 101000637950 Homo sapiens Transmembrane protein 127 Proteins 0.000 description 1
- 101000625727 Homo sapiens Tubulin beta chain Proteins 0.000 description 1
- 101000788517 Homo sapiens Tubulin beta-2A chain Proteins 0.000 description 1
- 101000713613 Homo sapiens Tubulin beta-4B chain Proteins 0.000 description 1
- 101000834944 Homo sapiens Tubulin epsilon and delta complex protein 2 Proteins 0.000 description 1
- 101000809261 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 11 Proteins 0.000 description 1
- 101000740048 Homo sapiens Ubiquitin carboxyl-terminal hydrolase BAP1 Proteins 0.000 description 1
- 101000743490 Homo sapiens V-set and immunoglobulin domain-containing protein 2 Proteins 0.000 description 1
- 101000868398 Homo sapiens Voltage-dependent calcium channel gamma-7 subunit Proteins 0.000 description 1
- 101000782180 Homo sapiens WD repeat-containing protein 1 Proteins 0.000 description 1
- 101000782169 Homo sapiens Zinc finger protein 232 Proteins 0.000 description 1
- 102100031449 Hormonally up-regulated neu tumor-associated kinase Human genes 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 102100027735 Hyaluronan mediated motility receptor Human genes 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 108091058560 IL8 Proteins 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100023351 Integral membrane protein 2A Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102100039060 Interleukin enhancer-binding factor 2 Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 102100040066 Interleukin-27 receptor subunit alpha Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102100023133 Jupiter microtubule associated homolog 1 Human genes 0.000 description 1
- 102100022889 KN motif and ankyrin repeat domain-containing protein 3 Human genes 0.000 description 1
- 102100028340 Keratin, type II cuticular Hb1 Human genes 0.000 description 1
- 102100037694 Kinesin-like protein KIF20A Human genes 0.000 description 1
- 102100038406 Kinesin-like protein KIF23 Human genes 0.000 description 1
- 102100023424 Kinesin-like protein KIF2C Human genes 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- JLERVPBPJHKRBJ-UHFFFAOYSA-N LY 117018 Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCC3)=CC=2)C2=CC=C(O)C=C2S1 JLERVPBPJHKRBJ-UHFFFAOYSA-N 0.000 description 1
- 102100028047 Large proline-rich protein BAG6 Human genes 0.000 description 1
- 101000740049 Latilactobacillus curvatus Bioactive peptide 1 Proteins 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 241001124320 Leonis Species 0.000 description 1
- 102100040274 Leucine-zipper-like transcriptional regulator 1 Human genes 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102100033468 Lysozyme C Human genes 0.000 description 1
- 108091007767 MALAT1 Proteins 0.000 description 1
- 102100032514 MARCKS-related protein Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 229940124640 MK-2206 Drugs 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 102100024299 Maternal embryonic leucine zipper kinase Human genes 0.000 description 1
- 101710154611 Maternal embryonic leucine zipper kinase Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 102400001132 Melanin-concentrating hormone Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 102100027240 Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Human genes 0.000 description 1
- IVDYZAAPOLNZKG-KWHRADDSSA-N Mepitiostane Chemical compound O([C@@H]1[C@]2(CC[C@@H]3[C@@]4(C)C[C@H]5S[C@H]5C[C@@H]4CC[C@H]3[C@@H]2CC1)C)C1(OC)CCCC1 IVDYZAAPOLNZKG-KWHRADDSSA-N 0.000 description 1
- 102100037106 Merlin Human genes 0.000 description 1
- 102100026821 Mesoderm-specific transcript homolog protein Human genes 0.000 description 1
- 102100030819 Methylcytosine dioxygenase TET1 Human genes 0.000 description 1
- 108010050345 Microphthalmia-Associated Transcription Factor Proteins 0.000 description 1
- 102100030157 Microphthalmia-associated transcription factor Human genes 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000713869 Moloney murine leukemia virus Species 0.000 description 1
- 241000711408 Murine respirovirus Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100011750 Mus musculus Hsp90b1 gene Proteins 0.000 description 1
- 101100538893 Mus musculus Trap1a gene Proteins 0.000 description 1
- 101100107191 Mus musculus Znf532 gene Proteins 0.000 description 1
- 102100036658 N(G),N(G)-dimethylarginine dimethylaminohydrolase 2 Human genes 0.000 description 1
- OUSFTKFNBAZUKL-UHFFFAOYSA-N N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide Chemical compound O1C(C(C)(C)C)=CN=C1CSC(S1)=CN=C1NC(=O)C1CCNCC1 OUSFTKFNBAZUKL-UHFFFAOYSA-N 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- YALNUENQHAQXEA-UHFFFAOYSA-N N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester Chemical compound C1=CC2=CC(CN(CC)CC)=CC=C2C=C1COC(=O)NC1=CC=C(C(=O)NO)C=C1 YALNUENQHAQXEA-UHFFFAOYSA-N 0.000 description 1
- 102100031641 N-alpha-acetyltransferase 10 Human genes 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 102100023515 NAD kinase Human genes 0.000 description 1
- 238000011789 NOD SCID mouse Methods 0.000 description 1
- 102100029166 NT-3 growth factor receptor Human genes 0.000 description 1
- 102000007530 Neurofibromin 1 Human genes 0.000 description 1
- 108010085793 Neurofibromin 1 Proteins 0.000 description 1
- 102100021584 Neurturin Human genes 0.000 description 1
- 102100030830 Nicotinate-nucleotide pyrophosphorylase [carboxylating] Human genes 0.000 description 1
- 102100037369 Nidogen-1 Human genes 0.000 description 1
- 208000004485 Nijmegen breakage syndrome Diseases 0.000 description 1
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 108700031302 Nuclear Factor 45 Proteins 0.000 description 1
- 102100030991 Nucleolar and spindle-associated protein 1 Human genes 0.000 description 1
- BDUHCSBCVGXTJM-IZLXSDGUSA-N Nutlin-3 Chemical compound CC(C)OC1=CC(OC)=CC=C1C1=N[C@H](C=2C=CC(Cl)=CC=2)[C@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CC(=O)NCC1 BDUHCSBCVGXTJM-IZLXSDGUSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 102000016304 Origin Recognition Complex Human genes 0.000 description 1
- 108010067244 Origin Recognition Complex Proteins 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102100028069 P2Y purinoceptor 8 Human genes 0.000 description 1
- SUDAHWBOROXANE-VIFPVBQESA-N PD 0325901-Cl Chemical compound OC[C@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-VIFPVBQESA-N 0.000 description 1
- 102100037482 PMS1 protein homolog 1 Human genes 0.000 description 1
- PBBRWFOVCUAONR-UHFFFAOYSA-N PP2 Chemical compound C12=C(N)N=CN=C2N(C(C)(C)C)N=C1C1=CC=C(Cl)C=C1 PBBRWFOVCUAONR-UHFFFAOYSA-N 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 102100040884 Partner and localizer of BRCA2 Human genes 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 102100038824 Peroxisome proliferator-activated receptor delta Human genes 0.000 description 1
- 102100026169 Phosphatidylinositol 3-kinase regulatory subunit alpha Human genes 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 1
- 102100030926 Pleckstrin homology-like domain family A member 2 Human genes 0.000 description 1
- 102100029799 Polycomb group protein ASXL1 Human genes 0.000 description 1
- 102100030702 Polycomb protein SUZ12 Human genes 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100026970 Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial Human genes 0.000 description 1
- 102100022407 Probable 28S rRNA (cytosine(4447)-C(5))-methyltransferase Human genes 0.000 description 1
- WDVSHHCDHLJJJR-UHFFFAOYSA-N Proflavine Chemical compound C1=CC(N)=CC2=NC3=CC(N)=CC=C3C=C21 WDVSHHCDHLJJJR-UHFFFAOYSA-N 0.000 description 1
- 102100034836 Proliferation marker protein Ki-67 Human genes 0.000 description 1
- 102100027427 Proline/serine-rich coiled-coil protein 1 Human genes 0.000 description 1
- 102100040400 Proteasome subunit beta type-2 Human genes 0.000 description 1
- 102000055027 Protein Methyltransferases Human genes 0.000 description 1
- 108700040121 Protein Methyltransferases Proteins 0.000 description 1
- 101710150336 Protein Rex Proteins 0.000 description 1
- 102100037337 Protein SGT1 homolog Human genes 0.000 description 1
- 102100028077 Protein YIPF3 Human genes 0.000 description 1
- 102100035620 Protein phosphatase 1 regulatory subunit 12C Human genes 0.000 description 1
- 102100024606 Protein phosphatase 1 regulatory subunit 1A Human genes 0.000 description 1
- 102100030400 Protein sprouty homolog 2 Human genes 0.000 description 1
- 102100026845 Protein sprouty homolog 4 Human genes 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 102100038517 Pyridoxal kinase Human genes 0.000 description 1
- 102100039790 Ran-specific GTPase-activating protein Human genes 0.000 description 1
- 101710179353 Ran-specific GTPase-activating protein Proteins 0.000 description 1
- 101710180752 Ran-specific GTPase-activating protein 1 Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 102100029753 Reduced folate transporter Human genes 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 102100025335 Reticulocalbin-1 Human genes 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- 102100021443 Rho GTPase-activating protein 8 Human genes 0.000 description 1
- 102100026006 Ribonucleoside-diphosphate reductase subunit M2 Human genes 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- ZJUKTBDSGOFHSH-WFMPWKQPSA-N S-Adenosylhomocysteine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSCC[C@H](N)C(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZJUKTBDSGOFHSH-WFMPWKQPSA-N 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 102100037779 SCRIB overlapping open reading frame protein Human genes 0.000 description 1
- 102100035214 SEC14-like protein 1 Human genes 0.000 description 1
- 102100032667 SLAIN motif-containing protein 1 Human genes 0.000 description 1
- 102100029214 SLAM family member 8 Human genes 0.000 description 1
- 108091006778 SLC19A1 Proteins 0.000 description 1
- 101150086694 SLC22A3 gene Proteins 0.000 description 1
- 108091006947 SLC39A4 Proteins 0.000 description 1
- 108700028341 SMARCB1 Proteins 0.000 description 1
- 101150008214 SMARCB1 gene Proteins 0.000 description 1
- 101150063267 STAT5B gene Proteins 0.000 description 1
- 102100025746 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 Human genes 0.000 description 1
- 101100010298 Schizosaccharomyces pombe (strain 972 / ATCC 24843) pol2 gene Proteins 0.000 description 1
- 102100030058 Secreted frizzled-related protein 1 Human genes 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102100031163 Selenide, water dikinase 1 Human genes 0.000 description 1
- 102100034606 Serine hydroxymethyltransferase, mitochondrial Human genes 0.000 description 1
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 1
- 102100024474 Signal transducer and activator of transcription 5B Human genes 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102100026937 Soluble lamin-associated protein of 75 kDa Human genes 0.000 description 1
- 102100021915 Sperm-associated antigen 5 Human genes 0.000 description 1
- 102100021816 Splicing factor 3B subunit 3 Human genes 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- 241000272534 Struthio camelus Species 0.000 description 1
- 206010042566 Superinfection Diseases 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 102100037942 Suppressor of tumorigenicity 14 protein Human genes 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- 101150057140 TACSTD1 gene Proteins 0.000 description 1
- 101150080074 TP53 gene Proteins 0.000 description 1
- 239000005463 Tandutinib Substances 0.000 description 1
- 102100024813 Targeting protein for Xklp2 Human genes 0.000 description 1
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 1
- 102100031294 Thymic stromal lymphopoietin Human genes 0.000 description 1
- 102100034838 Thymidine kinase, cytosolic Human genes 0.000 description 1
- 102100026159 Tomoregulin-1 Human genes 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 102100028601 Transaldolase Human genes 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 102100033055 Transketolase Human genes 0.000 description 1
- 102100032072 Transmembrane protein 127 Human genes 0.000 description 1
- SHGAZHPCJJPHSC-NWVFGJFESA-N Tretinoin Chemical compound OC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NWVFGJFESA-N 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- 102100024717 Tubulin beta chain Human genes 0.000 description 1
- 102100036821 Tubulin beta-4B chain Human genes 0.000 description 1
- 102100026157 Tubulin epsilon and delta complex protein 2 Human genes 0.000 description 1
- 102100033254 Tumor suppressor ARF Human genes 0.000 description 1
- 102100038462 Ubiquitin carboxyl-terminal hydrolase 11 Human genes 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 102100032869 Voltage-dependent calcium channel gamma-7 subunit Human genes 0.000 description 1
- 102100036551 WD repeat-containing protein 1 Human genes 0.000 description 1
- 201000011032 Werner Syndrome Diseases 0.000 description 1
- 102100036976 X-ray repair cross-complementing protein 6 Human genes 0.000 description 1
- 101710124907 X-ray repair cross-complementing protein 6 Proteins 0.000 description 1
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
- 108091002437 YBX1 Proteins 0.000 description 1
- 102000033021 YBX1 Human genes 0.000 description 1
- 102100036549 Zinc finger protein 232 Human genes 0.000 description 1
- 102100023140 Zinc transporter ZIP4 Human genes 0.000 description 1
- ZYVSOIYQKUDENJ-ASUJBHBQSA-N [(2R,3R,4R,6R)-6-[[(6S,7S)-6-[(2S,4R,5R,6R)-4-[(2R,4R,5R,6R)-4-[(2S,4S,5S,6S)-5-acetyloxy-4-hydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-7-[(3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-4,10-dihydroxy-3-methyl-5-oxo-7,8-dihydro-6H-anthracen-2-yl]oxy]-4-[(2R,4R,5R,6R)-4-hydroxy-5-methoxy-6-methyloxan-2-yl]oxy-2-methyloxan-3-yl] acetate Chemical class COC([C@@H]1Cc2cc3cc(O[C@@H]4C[C@@H](O[C@@H]5C[C@@H](O)[C@@H](OC)[C@@H](C)O5)[C@H](OC(C)=O)[C@@H](C)O4)c(C)c(O)c3c(O)c2C(=O)[C@H]1O[C@H]1C[C@@H](O[C@@H]2C[C@@H](O[C@H]3C[C@](C)(O)[C@@H](OC(C)=O)[C@H](C)O3)[C@H](O)[C@@H](C)O2)[C@H](O)[C@@H](C)O1)C(=O)[C@@H](O)[C@@H](C)O ZYVSOIYQKUDENJ-ASUJBHBQSA-N 0.000 description 1
- LUJZZYWHBDHDQX-QFIPXVFZSA-N [(3s)-morpholin-3-yl]methyl n-[4-[[1-[(3-fluorophenyl)methyl]indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamate Chemical compound C=1N2N=CN=C(NC=3C=C4C=NN(CC=5C=C(F)C=CC=5)C4=CC=3)C2=C(C)C=1NC(=O)OC[C@@H]1COCCN1 LUJZZYWHBDHDQX-QFIPXVFZSA-N 0.000 description 1
- SPJCRMJCFSJKDE-ZWBUGVOYSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-[4-[bis(2-chloroethyl)amino]phenyl]acetate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 SPJCRMJCFSJKDE-ZWBUGVOYSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- XZSRRNFBEIOBDA-CFNBKWCHSA-N [2-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethyl] 2,2-diethoxyacetate Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)C(OCC)OCC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 XZSRRNFBEIOBDA-CFNBKWCHSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- CHZVHNZRFPALHO-UHFFFAOYSA-N [Br].[Na] Chemical compound [Br].[Na] CHZVHNZRFPALHO-UHFFFAOYSA-N 0.000 description 1
- 229950008805 abexinostat Drugs 0.000 description 1
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 description 1
- 229950002684 aceglatone Drugs 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 210000004504 adult stem cell Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 229940001007 aluminium phosphate Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003135 anti-embryonic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000014102 antigen processing and presentation of exogenous peptide antigen via MHC class I Effects 0.000 description 1
- 239000013059 antihormonal agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940045720 antineoplastic alkylating drug epoxides Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 210000004507 artificial chromosome Anatomy 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 210000004957 autophagosome Anatomy 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229940077840 beleodaq Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 229950005993 brivanib alaninate Drugs 0.000 description 1
- LTEJRLHKIYCEOX-OCCSQVGLSA-N brivanib alaninate Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@@H](C)OC(=O)[C@H](C)N)=C1 LTEJRLHKIYCEOX-OCCSQVGLSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- 108010047060 carzinophilin Proteins 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004970 cd4 cell Anatomy 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- TVFDJXOCXUVLDH-RNFDNDRNSA-N cesium-137 Chemical compound [137Cs] TVFDJXOCXUVLDH-RNFDNDRNSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- USVCWSAJUAARAL-MEMLXQNLSA-N chembl551064 Chemical compound C1=2C(N)=NC=NC=2N([C@@H]2C[C@H](C2)N2CCC2)C=C1C(C=1)=CC=CC=1OCC1=CC=CC=C1 USVCWSAJUAARAL-MEMLXQNLSA-N 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229950008249 chlornaphazine Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960001480 chlorozotocin Drugs 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000011340 continuous therapy Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 1
- 108010089438 cryptophycin 1 Proteins 0.000 description 1
- 108010090203 cryptophycin 8 Proteins 0.000 description 1
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000032459 dedifferentiation Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 229950003913 detorubicin Drugs 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- FKGKZBBDJSKCIS-UHFFFAOYSA-N diethyl-[[6-[[4-(hydroxycarbamoyl)phenyl]carbamoyloxymethyl]naphthalen-2-yl]methyl]azanium;chloride;hydrate Chemical group O.[Cl-].C1=CC2=CC(C[NH+](CC)CC)=CC=C2C=C1COC(=O)NC1=CC=C(C(=O)NO)C=C1 FKGKZBBDJSKCIS-UHFFFAOYSA-N 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000012361 double-strand break repair Effects 0.000 description 1
- 229950005778 dovitinib Drugs 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000037437 driver mutation Effects 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- AFMYMMXSQGUCBK-AKMKHHNQSA-N dynemicin a Chemical compound C1#C\C=C/C#C[C@@H]2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3[C@@]34O[C@]32[C@@H](C)C(C(O)=O)=C(OC)[C@H]41 AFMYMMXSQGUCBK-AKMKHHNQSA-N 0.000 description 1
- 210000003981 ectoderm Anatomy 0.000 description 1
- 230000005014 ectopic expression Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 229940056913 eftilagimod alfa Drugs 0.000 description 1
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 1
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 230000000408 embryogenic effect Effects 0.000 description 1
- 210000001900 endoderm Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229950002189 enzastaurin Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 230000004076 epigenetic alteration Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229950002973 epitiostanol Drugs 0.000 description 1
- 229960003388 epoetin alfa Drugs 0.000 description 1
- 229940089118 epogen Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- QSRLNKCNOLVZIR-KRWDZBQOSA-N ethyl (2s)-2-[[2-[4-[bis(2-chloroethyl)amino]phenyl]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CCOC(=O)[C@H](CCSC)NC(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 QSRLNKCNOLVZIR-KRWDZBQOSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N furocoumarin Natural products C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 238000003197 gene knockdown Methods 0.000 description 1
- 230000004547 gene signature Effects 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 238000010363 gene targeting Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 231100000118 genetic alteration Toxicity 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 238000011331 genomic analysis Methods 0.000 description 1
- 230000008826 genomic mutation Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 210000001654 germ layer Anatomy 0.000 description 1
- 229950010415 givinostat Drugs 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000009033 hematopoietic malignancy Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 108010051779 histone H3 trimethyl Lys4 Proteins 0.000 description 1
- 210000004293 human mammary gland Anatomy 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940075628 hypomethylating agent Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 101150095658 ilf2 gene Proteins 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229940065638 intron a Drugs 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 201000008632 juvenile polyposis syndrome Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229950001845 lestaurtinib Drugs 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 229940087875 leukine Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- MPVGZUGXCQEXTM-UHFFFAOYSA-N linifanib Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C(N)=NNC=3C=CC=2)=C1 MPVGZUGXCQEXTM-UHFFFAOYSA-N 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229950009246 mepitiostane Drugs 0.000 description 1
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 description 1
- 210000003716 mesoderm Anatomy 0.000 description 1
- 230000018748 mesodermal cell migration Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 238000010208 microarray analysis Methods 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- ZTFBIUXIQYRUNT-MDWZMJQESA-N mubritinib Chemical compound C1=CC(C(F)(F)F)=CC=C1\C=C\C1=NC(COC=2C=CC(CCCCN3N=NC=C3)=CC=2)=CO1 ZTFBIUXIQYRUNT-MDWZMJQESA-N 0.000 description 1
- 210000002894 multi-fate stem cell Anatomy 0.000 description 1
- 229940031348 multivalent vaccine Drugs 0.000 description 1
- 125000001446 muramyl group Chemical group N[C@@H](C=O)[C@@H](O[C@@H](C(=O)*)C)[C@H](O)[C@H](O)CO 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- WPOXAFXHRJYEIC-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2C3=CC(OC)=C(OCC4CCN(C)CC4)C=C3N=CN=2)=C1 WPOXAFXHRJYEIC-UHFFFAOYSA-N 0.000 description 1
- XQFINGFCBFHOPE-UHFFFAOYSA-N n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-3-[ethyl-[4-[2-methoxyethyl(methyl)amino]cyclohexyl]amino]-2-methyl-5-(3-morpholin-4-ylprop-1-ynyl)benzamide Chemical compound C=1C(C#CCN2CCOCC2)=CC(C(=O)NCC=2C(NC(C)=CC=2C)=O)=C(C)C=1N(CC)C1CCC(N(C)CCOC)CC1 XQFINGFCBFHOPE-UHFFFAOYSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- QRGHOAATPOLDPF-VQFNDLOPSA-N nanatinostat Chemical group N1=CC(C(=O)NO)=CN=C1N1C[C@@H]([C@@H]2NCC=3N=C4C=CC(F)=CC4=CC=3)[C@@H]2C1 QRGHOAATPOLDPF-VQFNDLOPSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 1
- 229940071846 neulasta Drugs 0.000 description 1
- 229940082926 neumega Drugs 0.000 description 1
- 229940029345 neupogen Drugs 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- YMVWGSQGCWCDGW-UHFFFAOYSA-N nitracrine Chemical compound C1=CC([N+]([O-])=O)=C2C(NCCCN(C)C)=C(C=CC=C3)C3=NC2=C1 YMVWGSQGCWCDGW-UHFFFAOYSA-N 0.000 description 1
- 229950008607 nitracrine Drugs 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 239000012740 non-selective inhibitor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical class O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 108010046821 oprelvekin Proteins 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 229940045681 other alkylating agent in atc Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007500 overflow downdraw method Methods 0.000 description 1
- 108700025694 p53 Genes Proteins 0.000 description 1
- 229940118537 p53 inhibitor Drugs 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 201000010279 papillary renal cell carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 108010044644 pegfilgrastim Proteins 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229920005547 polycyclic aromatic hydrocarbon Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 230000000270 postfertilization Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Inorganic materials [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229940029359 procrit Drugs 0.000 description 1
- 229960000286 proflavine Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940021993 prophylactic vaccine Drugs 0.000 description 1
- 230000000722 protumoral effect Effects 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229950010654 quisinostat Drugs 0.000 description 1
- 230000005258 radioactive decay Effects 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 238000011362 radionuclide therapy Methods 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- FECGNJPYVFEKOD-VMPITWQZSA-N resminostat Chemical compound C1=CC(CN(C)C)=CC=C1S(=O)(=O)N1C=C(\C=C\C(=O)NO)C=C1 FECGNJPYVFEKOD-VMPITWQZSA-N 0.000 description 1
- 229950002821 resminostat Drugs 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009919 saracatinib Drugs 0.000 description 1
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 1
- 229950000055 seliciclib Drugs 0.000 description 1
- 229950003647 semaxanib Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000019130 spindle checkpoint Effects 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 1
- 229950009893 tandutinib Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229950004186 telatinib Drugs 0.000 description 1
- 108010057210 telomerase RNA Proteins 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 230000005100 tissue tropism Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 101150117196 tra-1 gene Proteins 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- 150000003327 trichothecene derivatives Chemical class 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229950000212 trioxifene Drugs 0.000 description 1
- 108010064892 trkC Receptor Proteins 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 208000006542 von Hippel-Lindau disease Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0603—Embryonic cells ; Embryoid bodies
- C12N5/0606—Pluripotent embryonic cells, e.g. embryonic stem cells [ES]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/48—Reproductive organs
- A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
- A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N13/00—Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0696—Artificially induced pluripotent stem cells, e.g. iPS
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5156—Animal cells expressing foreign proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/48—Blood cells, e.g. leukemia or lymphoma
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/49—Breast
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/40—Nucleotides, nucleosides, bases
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/065—Modulators of histone acetylation
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/70—Enzymes
- C12N2501/72—Transferases (EC 2.)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2529/00—Culture process characterised by the use of electromagnetic stimulation
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Cell Biology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Developmental Biology & Embryology (AREA)
- Mycology (AREA)
- Biomedical Technology (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Reproductive Health (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Gynecology & Obstetrics (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Transplantation (AREA)
- Hematology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Pregnancy & Childbirth (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
USE OF A HISTONE DEACETYLASE INHIBITOR AND A POPULATION OF INACTIVATED PLURIPOTENT CELLS FOR TREATING CANCERS FIELD OF THE INVENTION: The present invention is in the field of oncology, and more specifically, the invention relates to an anticancer vaccine combined therapy.More particularly, the invention relates to methods of producing a composition comprising pluripotent cells presenting multiple neo-antigens and thereof useful in preparing the cancer cell vaccines.
BACKGROUND OF THE INVENTION: The majority of cancers result from random mutations arising during DNA replication in normal stem cells required during development and tissue maintenance. Cancer Stem Cells (CSCs) are heterogeneous and epigenetically plastic in a dynamic status. Tumor cells arising from CSCs are driven by simultaneous accumulation of mutations present on oncogenes, tumor suppressor genes and signaling pathways leading to clonal waves of tumor evolution. In the ‘clonal-evolution model’ the types of mutations will vary as cancer develops, so that individual cancer cells become increasingly transformed and aggressive. Mutations acquired in early tumor development are sustained in advanced disease.Changing over time, these mutations lead to oligo-clonal tumor expansion, and cancer cell resistance in association with a progressive immune editing and exhaustion. Mutational signature of cancer is highly associated with genomic instability. Mutations give rise to novel non-self neo-antigens with immunogenic epitope. However, since the tumor microenvironment is generally immunosuppressive, the host immune system is generally not able to properly destroy these cells and fight these cancers. The clinical benefits reported by T cell response with immune checkpoint inhibitors is well correlated with the mutation rate and mutation landscape of the tumors.Cancer stem cells (CSCs) represent a minor population of self-renewing cancer cells that contribute to tumor persistence and recurrence since they are frequently resistant to conventional treatments. CSCs initially discovered in hematopoietic malignancies were described in solid tumors from various origins including beast, glioblastoma, prostate, colon head and neck squamous cell carcinoma, ovarian bladder, lung, pancreatic cancer. CSCs have the characteristic of forming xenograph tumors in mice and tumor initiation capacity. In addition, they are radio-and chemo-resistant, contributing to lack of therapeutic response in patients. CSCs persistence thereby causes tumor relapse and/or metastasis following the completion of therapy. Several publications have shown a molecular link between tumor pathogenesis and the Embryonic Stem Cell (ESC) state. CSC express a large number of embryonic antigens that are also expressed by human Embryonic Stem Cells (hESCs) and human Induced Pluripotent Stem Cells (hiPSCs).Primarily OCT4, NANOG, and SOX2 transcription factors are master regulators and work together as part of a highly integrated network (related to c-myc and polycomb network) to drive the transition from a somatic cell to either a CSC or iPSC by using epigenetic machinery to remodel the chromatin through histone modification and DNA methylation. These factors are absent in normal adult stem cells. Embryonic stem cell-like gene expression and under-expression of Polycomb-regulated genes defining human pluripotent stem cell (ESC/IPSC) identity are associated in poorly differentiated human tumors with poor clinical outcome and distant recurrence after chemo-radiotherapy whatever the origin of cancers (breast, pancreas, bladder, lung, prostate, medulloblastoma ..). Poorly differentiated tumors with a "stemness" profile are related to mesenchymal traits on carcinoma cells with epithelial- mesenchymal "EMT" markers, low levels of MHC-I expression, immunosuppressive tumor microenvironment with pro-tumoral inflammatory leukocytes, stromal cells and macrophages. Tumor cells undergoing EMT acquire stemness properties and become CSC with the capacity to migrate very early throughout the organism and to persist in a dormant stage for long periods of time. CSCs act as a reservoir to seed and replenish the tumor compartment. They also expand by self-renewal, disseminating to different tissues, generating metastases. These CSCs share pluripotent embryonic gene signatures and are resistant to anti-cancer drugs and radiotherapy. They also escape immune anti-tumor defenses for the reasons indicated above (immune-depressive micro-environment).It was reported that foetal tissues can be used to immunize mice and that this can induce the rejection of transplanted tumors, including cancer of the skin, liver, and gastrointestinal tract. This response has been explained by the fact that those tumor cells express a high number of oncofetal antigens.To date several human cancer vaccine trials have been set up in order to target embryonic antigens such as carcinoembryonic antigen (CEA), alpha fetoprotein or cancer/testes antigens. Unfortunately, targeting one antigen alone was shown to be not efficient enough to generate strong antitumor immune responses to mediate tumor rejection because of rapid appearance of escape mutants leading to the general inefficiency of monovalent cancer vaccines.
Recent interest in the potential of stem cells in regenerative medicine has made well- defined ESC lines widely available as well as iPSCs that are phenotypically and functionally similar to ESCs.Cancer-associated epigenetic aberrations are a characteristic trait of cancer stem cells involving every component of epigenetic machinery (DNA methylation, histone modifications, non-coding RNAs, specifically microRNA expression).Several epigenetic modifying drugs with tumor-inhibiting activities, are currently in clinical use in oncology, including hypomethylating agents such as azacitidine or decitabine and histone deacetylase inhibitors such as vorinostat or romidepsin.Using such drugs, it was possible to reprogram cancer cells. In addition, epigenetic reprogramming of the tumor micro-environment by epigenetic drugs is an attractive manipulating approach of cancer therapy as there is clear evidence of cancer-stroma interaction in cancer development.Thus, there continues to be a need for new approaches to prevent and/or treat cancers having stem cells signature. These cancers express a set of embryonic genes (i.e also called neo-antigens) in common with ESC/IPSC, and include, in particular, pancreatic cancer, breast cancer, ovarian, colon cancer, lung kidney, prostate carcinomas, medulloblastoma, cholangiocarcinoma, liver cancer, chronic and acute leukemias and myeloma. This class of cancer is mostly associated with a mesenchymal like-signature which needs to develop therapies targeting specifically the CSCs for improving survival and enhancing quality of life of cancer patients. In particular such strategies should lead to the restoration of a permissive anti-tumor micro-environment (the tumor micro-environment is generally immunosuppressive and thus should be remade immuno-competent) combined with an immune anti- CSC response. This and other needs are addressed in whole or in part by the presently disclosed subject matter.
SUMMARY OF THE INVENTION: The present invention is based on the determination, by the inventors, that HDACi (Histone deacetylase inhibitors) can be used to stimulate an immune response in a patient, against an antigen of interest, when an immunogenic composition, containing said antigen of interest, or targeting said antigen of interest, is administered to the patient, in combination with an HDACi, optionally followed by a further treatment with an HDACi. The immunogenic composition is intended to allow the onset of an immune response against (an) antigen(s) of interest. The use of HDACi as an adjuvant is particularly interesting for treatment of cancers, in particular for cancers having stem cell signature. The present invention is defined in particular by the claims.
DETAILED DESCRIPTION OF THE INVENTION: The inventors have shown that use of an HDACi together with a population of pluripotent cells led to a synergy and an efficient response of the immune system against tumor cells.Indeed, the inventors further hypothesized that pluripotent stem cells such as hESCs or hiPSCs could be used as a vaccine to generate an immune response against a variety of embryonic antigens that are shared by tumor cells. They found, that the vaccination of mice with hESCs or hiPSCs in combination with a compound that is able to induce MHC I, such as valproic acid was able to induce efficient immune and anti-tumoral responses against breast carcinoma without evidence of side effects and autoimmune diseases. In addition they found that this combined regimen was associated with a significant inhibition of lung metastasis. Surprisingly, they established that these responses are greatly improved by the addition of HDACI, and in particular valproic acid in the therapeutic regimen in comparison to the use of ESCs or iPSCs alone.
HDACi for improving immune response The invention relates to a method for increasing efficacy, in a patient, of a vaccine composition, comprising the step of administering an HDACi to the patient together with the vaccine composition. In particular, the HDACi can be added to the vaccine composition.Increased efficacy can be understood as increasing immunogenicity of the vaccine composition, increasing the immune response against the vaccine composition, or increasing the immune response generated by the vaccine composition. This can be compared to the immune response generated in the absence of HDACi.The vaccine composition contains an immunogenic element intended to make the patient develop an immune response against one or more antigen(s) of interest. An antigen of interest are any antigen against which an immune response is desired, and include any peptide, protein either from the self (such as antigens from cancer cells) or exogenous such as bacterial, viral, or parasitic protein, other kind of antigens such as nucleic acids, sugars, lipopolysaccharides and the like.The invention thus relates to the use of a HDACi as an adjuvant, in particular for increasing the immune response against a vaccine composition, as well as to HDACi for its use as an adjuvant, or for increasing the immune response against a vaccine composition. The invention also relates to the use of an HDACi for the manufacture of a vaccine composition containing one or more antigen(s) of interest, intended to have the patient develop an immune response against the antigen(s) of interest.The method and use herein disclosed are particularly interesting when the vaccine composition is a cancer vaccine composition, i.e. contains antigen(s) of interest that are expressed by cancer cells. In particular, the method and use are very adapted for solid tumor cancers. Indeed, in these types of cancers, the immune micro-environment is particularly immunosuppressive (i.e. there are an expression of cytokines and of molecular signals, and recruitment of such CD4 cells, that the potency of immune cells against the cancer antigens is decreased); without being bound by this theory, it is postulated the presence of the HDACi will modify the micro-environment and allow the immune cells to be potentiated to fight the cancer cells, probably by modifying expression of the genes that have an immunosuppressive effect in the cells that are present in, near or around the tumor.The method herein described may also comprise the step of administering an HDACi for a few days after the administration of the vaccine composition. This continuous administration of an HDACi can be useful for maintaining the microenvironment modification for a time long enough for the immune cells to be able to "take over" the tumor. Generally, this further continuous administration of the HDACi will consist in a daily administration of an adequate dose of the HDACi, for at least three days following vaccine administration, and up to one month. It is, however preferred when the further HDACi administration is performed for at least one week, more preferably at least or about two weeks.
The vaccine composition contains an immunogenic element (compound) intended to make the patient develop an immune response against one or more antigen(s) of interest.This immunogenic element may be an antigen (or multiple antigens). This antigen can be, as seen above, of any form, depending on the target cells (which is intended to include host cells, as well as bacterial cells, parasitic pathogens or viral particles). It can also be formulated with any adjuvant (immune-stimulant) known in the art such as alum or Freund’s complete or incomplete adjuvants.In another embodiment, the immunogenic compound is an extract from a cell composition, wherein cells of said composition express an antigen of interest. The cellular extract may be lysed cells that have been centrifuged to remove insoluble matter such as membrane fragments, vesicles, and nuclei, and thus consist mostly of cytosol. In another embodiment, the extract may have been made using specific techniques to deplete or enrich specific components (for example sonication can be used to break large membrane fragments into small particles that remain in the extract, or high speed centrifugation to remove the smallest insoluble components). The cell extract is obtained by any chemical or mechanical action, such as by pressure, distillation, evaporation and the like.In another embodiment the immunogenic element is a cell composition, wherein cells of said composition express the antigen of interest. In this embodiment, it is preferred when the membrane of the cells is preserved (so that presentation of the antigen is made through the MHC-I pathway). It is preferred when the cells are inactivated, as described below.In these embodiments, the cells may be pluripotent cells, as described below, cancer cells, virus-infected cells or bacterial cells.In another embodiment the immunogenic element is a cell composition comprising Antigen-Presenting-Cells (APCs) that have been primed in vitro by antigens of interest. This composition is an antigen-presenting cell vaccine, made of antigens and antigen-presenting cells (APCs). Antigen-presenting cells are cells that display antigen complexed with major histocompatibility complexes (MHCs) on their surfaces. One can cite dendritic cells (DC), which are preferred in the context of the invention, as they are able to present antigen to both helper and cytotoxic T cells, macrophages, or B cells. These APCs may be natural cells, or engineered cells. One can, in particular, cite Eggermont et al (Trends in Biotechnology, 2014, 32, 9, 456-465) which review advances in developing artificial antigen-presenting cells. Methods of developing anti-cancer vaccines, using APCs, have been widely proposed in the art and are known by the person skilled in the art.In another embodiment, the immunogenic element does not actually contain an antigen, but consists in a composition of T cell lymphocytes that have been primed in vitro against the antigen of interest, for instance by exposure to Antigen-Presenting-Cells presenting the antigen of interest. Consequently, this composition is able to onset an immune response in vivo against the antigen of interest. This strategy can be called "adoptive transfer of T cells", and it is known that such adoptively transferred T cells persist for long periods of time in vivo and readily migrate between the lymphoid and vascular compartments (Bear et al, J Biomed Biotechnol. 2011;2011:417403; Melief et al, J Clin Invest. 2015;125(9):3401-3412).
In all these embodiments, an HDACi is administered in combination with the vaccine composition containing the immunogenic element. Said administration may be simultaneous, separate or sequential, as disclosed below for the embodiment where the immunogenic element is a composition of pluripotent cells. It is to be noted that all descriptions below, that are disclosed for the composition of pluripotent cells are equally applicable to the vaccines comprising any immunogenic element as disclosed above.The present specification emphasizes an HDAC inhibitor (in particular valproic acid), together with a composition of pluripotent cells, as such pluripotent cells express neoantigens that are also found in very aggressive cancers, as reminded above. Consequently, whatever the immunogenic element, it is preferred when the antigen of interest is a neo-antigen that is expressed by cancer cells, as described above and also below.In particular, the immunogenic element is a cell composition, wherein the cell composition has been obtained by expansion and inactivation of pluripotent cells, as further disclosed in details below.
Method of treating a subject suffering from a cancer with a combined preparation The present invention relates a method of treating a subject suffering from a cancer comprising a step of administration simultaneously, separately or sequentially to said subject a therapeutically amount of i) a population of pluripotent cells and ii) a compound selected from a group which activates MHC expression and/or immune response, as a combined preparation.In the preferred environment, the cells have been cultured so as to present neoantigens through the MHC I pathway and, in particular, some cells of the population present mutated. The compound used in combination with the cells may also preserve pluripotency of the cells. It is greatly preferred when the administration of the cells is followed by administration of a compound which activates MHC expression and/or immune response (preferably the same than the one that has been initially administered in combination, but potentially another one) to enhance immune response.
As used herein, the terms "treating" or "treatment" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at high predisposed risk of contracting cancer such as hereditary family cancer syndromes or suspected to have contracted a cancer as well as subject who are ill or have been diagnosed as suffering from a cancer or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a cancer or who ultimately may acquire the cancer, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of cancer or recurring cancer, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, (e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria (e.g., pain, disease manifestation, etc.).As used herein, the term "administration simultaneously" refers to administration of active ingredients by the same route and at the same time or at substantially the same time. The term "administration separately" refers to an administration of 2 active ingredients at the same time or at substantially the same time by different routes. The term "administration sequentially" refers to an administration of 2 active ingredients at different times, the administration route being identical or different.As used herein, the term "subject" refers to any mammals, such as a rodent, a feline, a canine, and a non-human and human primate. Particularly, in the present invention, the subject is a human afflicted with or susceptible to be afflicted with cancers which having an expression of pluripotent embryonic-like stem cell antigens.As used herein, the term "population" refers to a population of cells, wherein the majority (e.g., at least about 20%, preferably at least about 50%, more preferably at least about 70%, and even more preferably at least about 80%, and even more preferentially at least about 90%) of the total number of cells have the specified characteristics of the cells of interest (e.g. pluripotency markers for iPSC, ESC defined by international stem cell initiative including at least 96 markers (Adewumi et al, Nat Biotech 2007), and gene-expression based assay (PluriTest) ( FJ Muller, Nature Methods 2011).Particularly, the term "a population of pluripotent cells" refers to a population of cells where the characteristics of the cells is expression of the pluripotency markers for iPSC, or ESC. These cells are preferably selected from the group consisting of human embryonic stem cells (hESC), induced human pluripotent stem cells (hiPSC), allogeneic, xenogeneic or syngeneic/autologous stem cells.As used herein, the term "pluripotent" refers to cells with the ability to give rise to progeny that can undergo differentiation, under appropriate conditions, into all cell types derived from the three germ layers (endoderm, mesoderm, and ectoderm) with specific cell lineages characteristics. The term "pluripotent" includes normal embryonic stem cells (ESCs), or very small embryonic-like stem cells (VSELs) or engineered induced pluripotent stem cells (iPSCs), reprogrammed from all sources and cell origins of adult somatic cells (ASCs).Pluripotent stem cells contribute to tissues of a prenatal, postnatal or adult organism. Standard art-accepted tests are used to establish the pluripotency of a cell population such as the ability to form a teratoma in 8-12 week old SCID mice, and various pluripotent stem cell characteristics. More specifically, human pluripotent stem cells express at least some (at least three, more generally at least four or five), and optionally all, of the markers from the following non-limiting list: SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, TRA-2-49/6E, Alkaline phosphatase (ALP), Sox2, E-cadherin, UTF-I, Oct4, Lin28, Rex1, Nanog, TERC, TERT.Pluripotent stem cells traditionally arise from the blastocyst stage of embryonic development and have the ability to develop into all types of fetal and adult cells except perhaps for placenta. Embryonic pluripotent stem cells (ESC) generally can be isolated from a 50- to 150-cell, 4- to 5-day-old post-fertilization blastocyst. While ESCs are capable of indefinite ex vivo proliferation, they exist only transiently in vivo during embryogenesis. Various animal (including human) ESC lines, such as, for example, NIH approved cell line WAO9 human ESCs can be obtained commercially from WiCell Research Institute, Madison, Wis. Human ESC lines, such as Cecol-14, can be obtained commercially for example from Cecolfes, Bogota, Colombia. Of course, other embryonic stem cell lines may be used, if desired.As used herein, the term "Embryonic stem cell" refers to pluripotent cells of humans (i.e., hESC). The hESC are isolated from a pre-blastocyst stage embryo. In another embodiment, the hES cells are prepared by dedifferentiation of at least partially differentiated cells (e.g., multipotent cells) and are totipotent in practice. Methods of preparing hESC are well known and taught, for example, in U.S. Patent Nos. 5,843,780, 6,200,806, 7,029,913, 5,453,357, 5,690,926, 6,642,048, 6,800,480, 5,166,065, 6,090,622, 6,562,619, 6,921,632, and 5,914,268, U.S. Published Application No. 2005/0176707, International Application No. WO2001085917. In the context of the invention, the human embryonic stem cell (hESC) are generated without embryo destruction according to the technology as described in Chung et al 2008.As used herein, the term "induced pluripotent stem cell" refers to a pluripotent stem cell artificially derived from a non-pluripotent cell by a reprogramming procedure, using methods known in the art and initially disclosed by Yamanaka (in particular WO2012/060473, PCT/JP2006/324881, PCT/JP02/05350, US 9,499,797, US 9,637,732, US 8,158,766, US 8,129,187, US 8,058,065, US 8,278,104. In short, somatic cells are reprogrammed to induced pluripotent stem cells (iPSCs) by ectopic expression of defined factors such as Oct4, Sox2, Klf4 and c-My, or Oct4, Sox2, Lin28 and Nanog. In a particular embodiment, the induced pluripotent stem cells are derived from mammals in particular (but not limited to) rodents, pigs, cats, dogs, and non-human primates, and human.iPSCs have been successfully generated from somatic cells of various origins (fibroblast, blood cells, keratinoctytes…) and by using variable technologies (such as integrative lentivirus/ retrovirus and non integrative vectors such as sendaï of virus, episomal vectors, synthetic mRNA, Adenovirus, rAAV, recombinant proteins…) with or without small chemical compounds.Small molecules can be used to enhance induction and quality of mouse and human iPSCs by acting as epigenetic modifiers (i.e. modifying expression of some genes). As an illustration, one can cite BIX01294 (BIX, a G9a histone methyltransferase inhibitor), sodium butyrate (NaB, an histone deacetylase HDAC inhibitor) or S-adeno- sylhomocysteine (SAH, a DNA demethylation agent), 5-azacytidine (5-AZA, a DNA methyltransferase inhibitor), Valproic acid (VPA, another histone deacetylase inhibitors) also improves reprogramming and quality of normal iPSCs.Fully reprogramed bona-fide iPSC express similarly pluripotent genes than embryonic stem cells with self-renewal capacity and represent an unlimited stem cell (or stem cell like) resource.ESC and IPSC can be amplified iteratively during multiple and illimited passages allowing scalable stem cells resources. Pluripotency potential is actively maintained in permissive culture conditions, by preserving high level expression of pluripotency genes. These methods are known in the art.
Specific culture conditions and methods allow to replicate a stable genome, but some exome mutations and epigenomic modifications have nevertheless been described (Gore A and al. Nature 2011).
As used herein, the term "somatic cell" refers to any cell of the body except germline cells (sperm and egg).As used herein, the term "allogeneic cells" refers cells from the same species but genetically distinct.As used herein, the term "syngeneic or autologous cells" refers to cells from the same species and the same genetic background.As used herein, the term "xenogeneic cells" refers to cells from different species and genetically distinct.In a particular embodiment, the stem cells can be derived from mammals but not limited to rodents, pigs, cats, dogs, and primates, including humans.
Method for producing a population of pluripotent cells: In a first aspect, the invention relates to a method for producing a cell composition, comprising the steps ofi) expanding pluripotent cells, in the presence of such conditions as to maintain the pluripotent ability of the cells, in the presence of an agent that induces MHC-I presentation of antigens in said population during the expansion stepii) Exposing the expanded cells to an inactivating agent that will inactivate the cells,iii) Recovering and conditioning the expanded inactivated cells.In a specific embodiment the cell envelope integrity is maintained in step ii).In another embodiment, the cells are inactivated and a cell derived product is obtained, such as cell extracts.The cell composition produced according to the method above can be used for cancer treatment, according to the methods disclosed herein.
Agent for MHC I antigen presentationPluripotent cells are expanded in the presence of an agent that will improve the presentation of antigens through the MHC I pathway. Such improved expression can be checked by comparing the number of MHC I molecules at the surface of the cells in the presence or in the absence of the agent.
Such agents are known in the art and one can cite, in particular histone deacetylase inhibitors (HDACis). Numerous products having this activity are known in the art, among these HDACis, one can cite, in particular valproate (VPA or valproic acid, CAS number 99-66-1). Other HDACis that can be used (as they have the same mode of action than VPA) are, in particular, vorinostat, romidepsin chidamide, panobinostat, belinostat, panobinostat, mocetinostat, abexinostat, entinostat, SB939, resminostat, givinostat or quisinostat.These agents are present in the cell culture (expansion) medium during the expansion of the pluripotent cells.
Maintaining the pluripotency of the cellsExpansion of the cells is performed in conditions so as to maintain the pluripotent ability of the cells (medium, temperature). These culture conditions are known in the art. Maintenance of the pluripotent ability of the cells will ensure that such cells will express (and hence present) all embryonic antigens, thereby increasing the capability of the cells of presenting such antigen at their surface through the MHC I pathway.The more embryonic antigens presented on the pluripotent cells surface, the increased probability that at least one of these antigens will also be present at the surface of the cancer cells, which will then be recognized and targeted by the immune system that will have been primed by the vaccine composition of the invention.Hence, maintenance of the pluripotency of the cells of the composition according to the invention, obtained by the methods herein disclosed, leads to presentation of a wide variety of embryonic antigens, and thus to the ubiquitous potency of the vaccine composition of the invention in the treatment methods herein disclosed.
Expansion of the cells in conditions such as to maintain pluripotency is known in the art. It is described, in particular, in all iPSC expansion protocols described to date (Shi Y and al, Nat Rev Drug Discovery 2017 ; Chen KG and al Cell Stem Cell. 2014). It is preferred when the following conditions are used:- Use of E8 medium or all clinical grade ES/iPSC culture medium, optionally supplemented with VPA and/or mutagen agents (such as ENU, see below).- Temperature of 37°C with or without hypoxia conditions- Change of the medium every day using the same medium with addition of VPA (from 0.1 mM to 5 mM) and/or ENU (0.1 µg/ml to 100 µg/ml) and/or p53 inhibitor and/or compound that enhance cell survival such as Y-27632 Rock inhibitor.
The cells are generally cultured for 8 weeks, with an optimal density of 90% maintained by regular passages once a week using enzymatic detachment (collagenase, trypsine).
Inactivating the cellsIn the preferred embodiment, the pluripotent cells that are used in the method of treatment herein disclosed are inactivated. The term "inactivated", and grammatical variants thereof, is used herein to refer to a cell (e.g., a pluripotent cell) that is alive but has been rendered incapable of proliferation (i.e., mitotically inactivated). The skilled in the art may use techniques that are known in the art including, but not limited to exposure to chemical agents, irradiation and/or lyophilization. Pluripotent cells can be inactivated such that upon administration to a subject the pluripotent cells are incapable of dividing and thus cannot form teratomas in the subject. It is understood that in the context of a plurality of cells, not every cell needs to be incapable of proliferation. Thus, as used herein the phrase "inactivated to an extent sufficient to prevent teratoma formation in the subject" refers to a degree of inactivation in the population as a whole such that after administration to a subject, a teratoma does not form since the irradiated pluripotent stem cells did not divide anymore as confirmed by in vitro culture. It is to be noted that, even if a one or more cells in the plurality of cells are in fact capable of proliferation in the subject, it is postulated that the immune system of the host will destroy those cells before a teratoma could form. Such inability of proliferation and teratoma formation may be confirmed by testing in mice having a functional and a nonfunctional immune system.In some embodiments, an "inactivated" cell is a killed cell, and in some embodiments, the inactivated cell is a whole cellular lysate, pluripotent stem cells derived exosomes, enriched cancer stem neo-antigens, a whole purified cancer stem neo-antigens, DNA RNA and protein extracts, a whole cells suspension that has been lyophilized, a fraction of a cellular lysate such as a membrane fraction, a cytoplasmic fraction, or a combination thereof. Inactivated pluripotent stem cells remain capable of stimulating immune response when the vaccination of mice is carried out with hESCs or hiPSCs in combination with valproic acid or another HDACi. This vaccination is able to induce efficient immune and anti-tumoral responses against 4T1 breast carcinoma without evidence of side effects and autoimmune diseases.Typically, to inactivate the stem cells, they can be exposed to lethal doses of radiation, (e.g., 5 to 100 Gy single fraction). The precise radiation dose delivered to the cells and length of dose are not critical so long as the cells are rendered nonviable.
Recovering and conditioning the cellsThe recovery step of the method includes one (or multiple) step(s) of washing the cell culture and resuspending the cells in any appropriate medium such as X-Vivo/Stemflex media or any other clinical grade cell media.The conditioning of the cells may include freezing or lyophilizing the cells, in order to be able to store the cell composition before use.
Mutating the pluripotent cells and expressing neo-antigens It is reminded that pluripotent cells are cells that are genetically very stable. Indeed, since they are present very early in the process of embryo development and they must multiply for embryo development, it is important that these cells are not too prone to mutations in order to have homogeneity in the embryo.Consequently cells present in a population of pluripotent cells are generally very homogenous when considering their genetic content (i.e. more than 95 % of the cells of the population present the same genetic background.When preparing iPSCs, a selective advantage of some cells occur during multiple passages, which leads to the population of iPSCs clones that present particular mutations at late passages, but the sequence of the cell genomes are similar close to 100 %.However, after several passages, iPSC are as stable as hESC (Hussein SM and al, Nature 2011). Culture-induced (adaptive) mutations will be acquired with a very few genetic changes upon prolonged culture (Hussein SM and al, Bioessays, 2012).It is however, favorable to be able to induce mutations in the cells in order to increase the variability of the fetal/embryonic neo-antigens on the treated cellular material that are found in the aggressive cancers. In this way it will increase the possibility for the immune system to generate T cells against these mutated cells and be able to fight cancer cells as well as those that would undergo later variation during growth of the tumor.This would help to fight the cancer that results from accumulation of genetic alterations resulting from DNA replication errors and/or environmental insults during proliferation of cancer stem cells. These alterations include cancer driver mutations that initiate carcinogenesis and genome destabilizing mutations. This increased genome instability results in clonal evolution leading to the selection of more aggressive clones with increased drug resistance.
Consequently, in a specific embodiment, the cells are expanded in conditions that will induce mutations in genes of said cells.The cells can thus be exposed to a mutagenic agent, i.e. a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level.The mutagen can be selected from the group consisting of physical mutagens and chemical mutagens.Among physical mutagens, one can cite- ionizing radiations such as X-rays, gamma rays and alpha particles which may cause DNA breakage and other damages. One can, in particular cite radiations from cobalt- and cesium-137. The level of irradiating rays shall be much lower the one that is used for cells inactivation and can be designed by the person skilled in the art- ultraviolet radiations with wavelength above 260 nm, which can cause error in replication if left uncorrected.- or radioactive decay, such as 14C in DNA.
Among chemical mutagens, one can cite- Reactive oxygen species (ROS), such as superoxide, hydroxyl radicals, hydrogen peroxide.- Deaminating agents, such as nitrous acid which can cause transition mutations by converting cytosine to uracil.- Polycyclic aromatic hydrocarbon (PAH), which can bind to DNA when activated to diol-epoxides.- Alkylating agents such as ethylnitrosourea (ENU, CAS number 759-73-9), mustard gas or vinyl chloride.- Aromatic amines and amides such as 2-Acetylaminofluorene- Alkaloid from plants, such as those from Vinca species- Bromine and some compounds that contain bromine- Sodium azide- Bleomycin- Psoralen combined with ultraviolet radiation- Benzene- Base analogs, which can substitute for DNA bases during replication and cause transition mutations - Intercalating agents, such as ethidium bromide, proflavine, daunorubicin- Metals, such as arsenic, cadmium, chromium, nickel and their compounds which may be mutagenic In this embodiment, one will obtain a population of pluripotent stem cells in which the cells have random mutations (generally different from cell to cell, thereby leading to a heterogeneous population), in particular in cancer related neo-antigens.The inventors have shown that it is possible to design culture conditions that make it possible to induce DNA replication errors in pluripotent stem cells without triggering DNA damagedependent apoptosis.This is particularly surprising as, as indicated above, pluripotent cells are naturally very stable for there should be as low number as possible mutations introduced during the early stages of embryogenesis. It results from this that the DNA repair machinery is very efficient in these cells, thereby correcting most defects and/or inducing apoptosis in case it is not possible to correct these defects.In one embodiment, pluripotent cells (such as ESCs or IPSCs) of a starting population are expanded and maintained in pluripotent permissive culture media (as known in the art) to preserve the pluripotent stage during iterative passages. In these conditions, one would generally observe a low amount of exome mutations (5-10 mutations per exome).The pluripotent cells are then cultured in vitro with mutagenesis compounds methods to induce and increase genomic instability within the pluripotent stem cells, such as the ones listed above. DNA damage is well confirmed by phosphorylation of γH2AX as a marker for Double-Strand Breaks (DSBs). Both proportion of γH2AX positive cells and frequency of γH2AX foci increased in ESCs or IPSCs as well as higher number of micronuclei as a mark of genomic instability.Preferred agents are Bleomycin, ENU, alkylating agents, Actinomycin D, ROS-modulating agents, UV, H2O2, ionizing radiations (gamma rays, X rays), which all allow the induction and enhancement of mutation rates in pluripotent stem cells that accumulate during culture.In a preferred embodiment, N-ethyl-N-nitrosourea (ENU) has been shown to create novel mutations and enhance the level of neo-antigens in treated pluripotent stem cells during long term culture at least from 7 to 60 days at a dose of <50 µg/ml. These mutations are similar to those reported in cancer.
It is thus possible to accumulate a diversity of mutations in response to DNA damage during pluripotent cells proliferation with a high rate of mutations from a selective advantage upon prolonged culture, while maintaining the pluripotency of the cells, in particular when the cells are cultured with HDACi in the medium. The presence of HDACis in culture preserves the increase active histones (H3K4me3 and H3K9ac) and epigenetic mark of pluripotency in response to inducing DNA damage, and the replication and proliferation rate during passages.
In another embodiment of the compositions and methods described herein, mutations are induced in the pluripotent cells through genetic modification of the cells with genes that promote high level of genomic instability. In particular, one can delete or reduce activity of genes or signaling pathways involved in DNA repair and replication, using appropriate inhibitors such as NER/BER/DSBR/MMR inhibitors. These methods that induce genomic instability linked to increased DNA damage may be performed by using "vectors" or by "genetic modification" that inactivate or knock down DNA repair related genes or signaling pathways such as DNA polymerase delta complex, mismatch repair (MMR), base excision repair (BER), Nucleotide excision repair (NER), homologous recombination (HR), DSBR or NEJH. Other examples of DNA repair genes are DNApkC, Ku70, Rad 51, Brca1 or Brca2.
In other embodiments, pluripotent cells are modified so as to repress apoptosis-associated genes such as p53 by genetic modification or chemical p53 such as Pifithrin-mu, Nutlin-3, or by using compounds that enhance cell survival such as Y-27632, a selective inhibitor of the p160-Rho-associated coiled kinase (ROCK).
In a particular embodiment, the population of pluripotent cells consists of induced pluripotent stem cells (iPSCs) that were generated from somatic cells, such as cells isolated from a patient, that already contained genomic alterations linkedi) to DNA repair diseases including for exemple Ataxia telangiectasia, Bloom syndrome, Cockayne's syndrome, Fanconi's anaemia, Werner syndrome, Xeroderma pigmentosum, Nijmegen breakage syndrome ;ii) to hereditary family cancer syndromes with genomic instability, such Lynch syndrome (hereditary non-polyposis colorectal cancer with mutations in MMR genes including MLH1, MSH2, MSH6, PMS1, and PMS2), Li-Fraumeni with mutation in the TPgene or CHEK2 , Hereditary Breast and Ovarian Cancer (HBOC) syndrome with deletion or mutation in BRCA1/2 gene, familial adenomatous polyposis (FAP) with mutations in APC gene ;iii) somatic oncogenic induced genomic instability as in CML with a translocation (T 9;22).In a preferred embodiment, the population of mutated pluripotent cells is made of induced pluripotent stem cells and generated from somatic cells containing genomic alterations linked to a disease. Typically, genomic alterations could be a translocation (T9:22), a deletion (BRCA1/2) or mutations (BRCA, RET).In a particular embodiment, the population of pluripotent stem cells consists of iPSCs generated from cancer cell lines or patient- specific cancer cells.
In another embodiment, the population of ESCs or IPSCs is modified genetically to overexpress multiple non-random cancer stem related neo-antigens by using « vectors ». In particular embodiment, the population of ESCs or IPSCs is modified genetically to express multiple mutations and cancer stem cell specific neo-antigens (at least 5) in pluripotent stem cells by "genome editing" technology. The present invention provides compositions and methods providing ESCs or IPSCs by introducing of multiple neo-antigens thereof by RNA- guided multiplex genome editing, modification, inhibition of expression and other RNA- based technologies.The term "genome editing" used here refers to the RNA mediated genetic manipulation including, in particular, a guide RNA for cas9-mediated genome editing. This guide RNA, (gRNA) is transfected along with an endonuclease cas9. The guide RNA provides the scaffold and a spacer sequence complementary to the target. In another embodiment genetic manipulation sequence can be a siRNA or a microRNA sequence designed for gene silencing according to standard methods in the art by the use of Crispr-Cas 9 systems. Compositions and methods for making and using Crispr-Cas systems are known in the art and described, in particular, in U.S. 8,697,359.
In a particular embodiment, the population of pluripotent cells is treated with alkylating agents. As used herein, the term "alkylating agents" refers to a substance which adds one or more alkyl groups from one molecule to another. This treatment creates new mutations in neo-antigens providing superior immune reactions by increasing oligo clonal expansion of TILs and Th1/Th2 cellular immunity.
In the present invention, an alkylating agent is selected from the group consisting of nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines, ethylenimines, and combinations thereof. Non-limiting examples of nitrogen mustards include mechlorethamine (Lundbeck), chlorambucil (GlaxoSmithKline), cyclophosphamide (Mead Johnson Co.), bendamustine (Astellas), ifosfamide (Baxter International), melphalan (Ligand), melphalan flufenamide (Oncopeptides), and pharmaceutically acceptable salts thereof. Non-limiting examples of nitrosoureas include streptozocin (Teva), carmustine (Eisai), lomustine (Sanofi), and pharmaceutically acceptable salts thereof. Non-limiting examples of alkyl sulfonates include busulfan (Jazz Pharmaceuticals) and pharmaceutically acceptable salts thereof. Non-limiting examples of triazines include dacarbazine (Bayer), temozolomide (Cancer Research Technology), and pharmaceutically acceptable salts thereof. Non-limiting examples of ethylenimines include thiotepa (Bedford Laboratories), altretamine (MGI Pharma), and pharmaceutically acceptable salts thereof. Other alkylating agents include ProLindac (Access), Ac-225 BC-8 (Actinium Pharmaceuticals), ALF-2111 (Alfact Innovation), trofosfamide (Baxter International), MDX-1203 (Bristol-Myers Squibb), thioureidobutyronitrile (CellCeutix), mitobronitol (Chinoin), mitolactol (Chinoin), nimustine (Daiichi Sankyo), glufosfamide (Eleison Pharmaceuticals), HuMax-TAC and PBD ADC combinations (Genmab), BP-C1 (Meabco), treosulfan (Medac), nifurtimox (Metronomx), improsulfan tosilate (Mitsubishi tanabe Pharma), ranimustine (Mitsubishi tanabe Pharma), ND-(NanoCarrier), HH-1 (Nordic Nanovector), 22P1G cells and ifosfamide combinations (Nuvilex), estramustine phosphate (Pfizer), prednimustine (Pfizer), lurbinectedin (PharmaMar), trabectedin (PharmaMar), altreatamine (Sanofi), SGN-CD33A (Seattle Genetics), fotemustine (Servier), nedaplatin (Shionogi), heptaplatin (Sk Holdings), apaziquone (Spectrum Pharmaceuticals), SG-2000 (Spirogen), TLK-58747 (Telik), laromustine (Vion Pharmaceuticals), procarbazine (Alkem Laboratories Ltd.), and pharmaceutically acceptable salts thereof. In another embodiment, the alkylating agent is selected from the group consisting of mechlorethamine (Lundbeck), chlorambucil (GlaxoSmithKline), cyclophosphamide (Mead Johnson Co.), streptozocin (Teva), dacarbazine (Bayer), thiotepa (Bedford Laboratories), altretamine (MGI Pharma), pharmaceutically acceptable salts thereof, and combinations thereof. In another embodiment, the alkylating agent is selected from the group consisting of ProLindac (Access), Ac-225 BC-8 (Actinium Pharmaceuticals), ALF-2111 (Alfact Innovation), bendamustine (Astellas), ifosfamide (Baxter International), trofosfamide (Baxter International), MDX-1203 (Bristol-Myers Squibb), temozolomide (Cancer Research Technology), thioureidobutyronitrile (CellCeutix), mitobronitol (Chinoin), mitolactol (Chinoin), nimustine (Daiichi Sankyo), carmustine (Eisai), glufosfamide (Eleison Pharmaceuticals), HuMax-TAC and PBD ADC combinations (Genmab), busulfan (Jazz Pharmaceuticals), melphalan (Ligand), BP-C1 (Meabco), treosulfan (Medac), nifurtimox (Metronomx), improsulfan tosilate (Mitsubishi tanabe Pharma), ranimustine (Mitsubishi tanabe Pharma), ND-01 (NanoCarrier), HH-1 (Nordic Nanovector), 22P1 G cells and ifosfamide combinations (Nuvilex), melphalan flufenamide (Oncopeptides), estramustine phosphate (Pfizer), prednimustine (Pfizer), lurbinectedin (PharmaMar), trabectedin (PharmaMar), altreatamine (Sanofi), lomustine (Sanofi), SGN-CD33A (Seattle Genetics), fotemustine (Servier), nedaplatin (Shionogi), heptaplatin (Sk Holdings), apaziquone (Spectrum Pharmaceuticals), SG-2000 (Spirogen), TLK-58747 (Telik), laromustine (Vion Pharmaceuticals), procarbazine (Alkem Laboratories Ltd.), pharmaceutically acceptable salts thereof, and combinations thereof.In a particular embodiment, the population of pluripotent cells is treated with N-ethyl-N- nitrosourea (ENU, CAS Number 759-73-9). ENU has the following chemical formula C3H7N3O2, is a highly potent mutagen by transferring the ethyl group to nucleobases in nucleic acids.As indicated above, the purpose of the mutagenic agent is to introduce random mutations in genes of the pluripotent cells during expansion (introduction of mutations occurs during the replication and division of the cells). The population of pluripotent stem cell acquires mutations that may provide a growth advantage and are selected for to promote culture adaptation. Passages of ESCs or iPSCs undergo a high level of selection pressure, and upon expansion multiple clonal mutated population may be favorably selected for.It is to be noted that, since the pluripotent cells are very stable, application of the mutagen may have to be performed for a long period of time. As a matter of illustration, when ENU is used, it may be applied for at least 7 days, more preferably at least 15 days, more preferably at least 20 days, more preferably at least 30 days, more preferably at least 40 days, more preferably at least 50 days or even at least 60 days. After application of the mutagen, the cells are washed (if the mutagen is a chemical agent) and can be further expanded, in the presence of the agent that favors MHC-I expression, in particular a HDACi. This agent is preferably also present during application of the mutagenic agent.
It can thus be observed and checked that the mutagen will induce mutations (i.e non- synonymous, nonsense, frameshift, StopGain, splice variant, CNVs , SNVs) in some of the embryogenic genes that are expressed by the pluripotent cells and hence increase the diversity of these antigens (new neo-antigens within the whole genome). This will thus increase the possibility of the vaccine composition with enhanced immunogenicity, able to stimulate a broad immune response against aggressive cancers where there are rapid and frequent mutations.
An efficient immune response may indeed be difficult to obtain for some cancer where clonal expansion of cancer cells occurs with mutations in the antigens expressed by the tumor cells. The immune response would thus depend in the mutational load of the cancer. The generation of random mutations in the pluripotent cell population by the use of the mutagen would thus lead to expression of mutated embryonic antigens and increase the diversity of the antigens presented to the immune system upon vaccination.Consequently, there would already be primed T-cells against mutated antigens that would appear in the cancer cells during division of such cells, which would speed-up and improve the immune response against these cells.
Modification of pluripotent cellsIn a particular embodiment, the population of pluripotent stem cells is modified genetically to over-express compounds which stimulate immune response by using gene integration within the pluripotent cell genome. Typically, in the first step, the population of stem cells is isolated and expanded. In the second step, the genes of interest are packaged into integrative viral vectors, such as retroviruses or lentiviruses. In the third step, integrative viral vectors containing the interest gene are transferred to the population of stem cells.In a particular embodiment, the population of pluripotent cells is modified with the genes of proteins which stimulate MHC expressions and/or immune response. These compounds are selected from the group consisting of interferon alpha (IFN-α), an interferon gamma (IFN-γ), an interleukin 2 (IL-2), an interleukin 4 (IL-4), an interleukin 6 (IL-6), an interleukin 12 (IL-12), a tumor necrosis factors (TNFs), and a granulocyte-macrophage colony stimulating factor (GM-CSF), functional fragments thereof, and combinations thereof.Interferons (IFNs) contemplated by the present invention include the common types of IFNs, IFN-alpha (IFN-α), IFN-beta (IFN-β) and IFN-gamma (IFN-γ). IFNs can act directly on cancer cells, for example, by slowing their growth, promoting their development into cells with more normal behavior and/or increasing their production of antigens thus making the cancer cells easier for the immune system to recognize and destroy. IFNs can also act indirectly on cancer cells, for example, by slowing down angiogenesis, boosting the immune system and/or stimulating natural killer (NK) cells, T cells and macrophages. Recombinant IFN-alpha is available commercially as Roferon (Roche Pharmaceuticals) and Intron A (Schering Corporation).Interleukins contemplated by the present invention include IL-2, IL-4, IL-11 and IL-12. Examples of commercially available recombinant interleukins include Proleukin® (IL-2; Chiron Corporation) and Neumega® (IL-12; Wyeth Pharmaceuticals). Zymogenetics, Inc. (Seattle, Wash.) is currently testing a recombinant form of IL-21, which is also contemplated for use in the combinations of the present invention.Colony-stimulating factors (CSFs) contemplated by the present invention include granulocyte colony stimulating factor (G-CSF or filgrastim), granulocyte-macrophage colony stimulating factor (GM-CSF or sargramostim) and erythropoietin (epoetin alfa, darbepoietin). Treatment with one or more growth factors can help to stimulate the generation of new blood cells in subjects undergoing traditional chemotherapy. Accordingly, treatment with CSFs can be helpful in decreasing the side effects associated with chemotherapy and can allow for higher doses of chemotherapeutic agents to be used. Various-recombinant colony stimulating factors are available commercially, for example, Neupogen® (G-CSF; Amgen), Neulasta (pelfilgrastim; Amgen), Leukine (GM-CSF; Berlex), Procrit (erythropoietin; Ortho Biotech), Epogen (erythropoietin; Amgen), Arnesp (erytropoietin).
In its broadest sense, a "vector" is any vehicle capable of facilitating the transfer of the oligonucleotides to the cells. Preferably, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector. In general, the vectors useful in the invention include, but are not limited to, naked plasmids, non-viral delivery systems (electroporation, sonoporation, cationic transfection agents, liposomes, etc…), phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the nucleic acid sequences. Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: RNA viruses such as a retrovirus (as for example moloney murine leukemia virus and lentiviral derived vectors), harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno- associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus. One can readily employ other vectors not named but known to the art.
Typically, in the context of the invention, viral vectors include adenoviruses and adeno-associated (AAV) viruses, which are DNA viruses that have already been approved for human use in gene therapy. Actually 12 different AAV serotypes (AAV1 to 12) are known, each with different tissue tropisms (Wu, Z Mol Ther 2006; 14:316-27). Recombinant AAV are derived from the dependent parvovirus AAV (Choi, VW J Virol 2005; 79:6801-07). The adeno-associated virus type 1 to 12 can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species (Wu, Z Mol Ther 2006; 14:316-27). It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hematopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions. In addition, wild-type adeno-associated virus infections have been followed in tissue culture for greater than 1passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event. The adeno-associated virus can also function in an extrachromosomal fashion.Other vectors include plasmid vectors. Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g. Sambrook et al., 1989. In the last few years, plasmid vectors have been used as DNA vaccines for delivering antigen-encoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors. These plasmids, however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid. Some commonly used plasmids include pBR322, pUC18, pUCl9, pRC/CMV, SV40, and pBlueScript. Other plasmids are well known to those of ordinary skill in the art. Additionally, plasmids may be custom designed using restriction enzymes and ligation reactions to remove and add specific fragments of DNA. Plasmids may be delivered by a variety of parenteral, mucosal and topical routes. For example, the DNA plasmid can be injected by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by ,intranasal sprays or drops, rectal suppository and orally. Preferably, said DNA plasmid is injected through an intraocular way (intravitreal, sub retinal, suprachoroidal...). It may also be administered into the epidermis or a mucosal surface using a gene-gun. The plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and microencapsulation.
In a particular embodiment, the population of stem cells is modified by the introduction of the transgene such as siRNA into the AAVS1 locus of chromosome 19 by homologous recombination.The term "homologous recombination" as used herein refers to a gene targeting means for artificially modifying a specific gene on a chromosome or a genome. When a genomic fragment having a portion homologous to that of a target sequence on the chromosome is introduced into cells, the term refers to recombination that takes place based on the nucleotide sequence homology between the introduced genomic fragment and the locus corresponding thereto on the chromosome.
Also, the term "genetic modification" refers to, in the locus of a desired gene on the chromosome, the insertion of an exogenous DNA, the substitution of a portion of or the whole of the gene with an exogenous DNA, or the deletion of the gene. More specifically, genetic modification refers to the insertion (that is, "knock-in") of an exogenous DNA fragment while the endogenous DNA sequence is retained in a manner such that the fragment is expressed in conjunction with the expression of a gene at a specific locus or is expressed constitutively, or, the substitution, deletion, or disruption (that is, "knock-out") of a portion of or the whole gene sequence so as to modify the endogenous DNA sequence.Examples of methods for introducing an artificial chromosome into cells include a calcium phosphate precipitation method (Graham et al., (1978) Virology 52: 456-457, Wigler et al., (1979) Proc. Natl. Acad. Sci. U.S.A. 76 1373-1376 and Current Protocols in Molecular Biology Vol.1, Wiley Inter-Science, Supplement 14, Unit 9.1.1-9.1.9 (1990)), a fusion method using polyethylene glycol (U.S. Pat. No. 4,684,611), a method using lipid carriers such as lipofection (Teifel et al., (1995) Biotechniques 19: 79-80, Albrecht et al., (1996) Ann. Hematol. 72: 73-79; Holmen et al., (1995) In Vitro Cell Dev. Biol. Anim. 31: 347-351, Remy et al., (1994) Bioconjug. Chem. 5: 647-654, Le Bolc'het al., (1995) Tetrahedron Lett. 36: 6681-6684, Loeffler et al., (1993) Meth. Enzymol, 217: 599-618 and Strauss (1996) Meth. Mol. Biol. 54: 307-327), electroporation, and methods for fusion with microcells (U.S. Pat. Nos. 5,240,840, 4,806,476, 5,298,429, and 5,396,767, Fournier (1981) Proc. Natl. Acad. Sci. U.S.A. 78: 6349-6353 and Lambert et al., (1991) Proc. Natl. Acad. Sci. U.S.A. 88: 5907-59).
Population of cells Thus, with the methods as described above, the inventors have obtained a population of pluripotent cells expressing new embryonic epitopes within partial or all the embryonic genes that will trigger a more efficient antitumor immunity. More particularly, the inventors have shown that the population of pluripotent cells treated with N-ethyl-N-nitrosourea (ENU) presents random mutations compared to the population of pluripotent cells without treated with ENU. Accordingly, this population is also a subject of the invention.The invention thus relates to a composition of cells comprising pluripotent cells, wherein cells in said population presents a mutation rate of at least 0.1%, preferably at least 1%, more preferably at least 2%, more preferably at least 5%, more preferably at least 10%, more preferably at least 15%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40%, or even at least 50%, in at least three genes, more preferably at least four genes, more preferably at least five genes, more preferably at least six genes, more preferably at least seven genes, selected from the following group consisting of TP53, P2RY8, CRLF2, CRTC3, BLM, ASXL1, IDH2, NTRK3, MALAT1, EXT1, NCOA2, IKF1, PIK3R1, EP300,AKT2, PPP2R1A, CDK12, BRCA1, ERB2, , CDH1, TBX3, SMARCD1, HSP90AA1, EZH2, SUZ12, STAT5B and POUF5F1.This mutation rate of the genes is studied in the cell population, after exposure to the mutagenic agent, before or after further expansion, if such further expansion is performed.Due to the fact that the pluripotent cells are genetically very stable, the presence of a high amount of mutations in at least three genes as listed above demonstrates the presence of a new population of pluripotent cells that didn’t preexist and would not be observed in the absence of the mutagenic conditions.Exposure of the cells to the mutagenic agent will trigger apparition of random mutations in the genome of such cells. The population resulting from such exposure will thus be heterogeneous, as compared to a population of pluripotent cells that is essentially homogenous, due to the low rate of natural mutations during long term expansion and culture. The population herein obtained is thus characterized in particular in that: - The cells are pluripotent (i.e. bear the markers of pluripotency)- There are multiple differences in the genome of the cells in the population, as indicated above, i.e. it is possible to detect a rate (as indicated above) of mutated genes as listed above, within the cells of the population.As a matter of illustration, a mutation rate of 5 % of the TP53 gene means that 95 % of the TP53 sequences in the cell population are identical (called TP53 reference sequence), and the last 5 % of the TP53 sequence are different from the TP53 reference sequence.
In a further embodiment, the invention thus relates to a composition of cells comprising pluripotent cells, wherein cells in said population present a mutational landscape in the population of ESCs or IPSCs comprising one or more of the following features:i) At least > 3 (or more as seen above) cancer related neo-antigens mutations introduced genetically in ESCs or IPSCs by genomic modification.ii) A combination of mutation types restricted to cancer genome induced by mutagen agents and enriched by a selective advantage in cultured embryonic pluripotent stem cells.
Mutagen process is causing increased levels of novel genomic mutations and genetic mosaicism in the resultant late-passage human iPS cell lines.Analysis of the mutations in the genes is preferably performed by large scale genomic analysis of induced cancer related "mutanome" signature, in each ESCs and IPSCs population, by NGS (Exome, RNAseq or Whole-genome sequencing), CGH array, SNP arrays. Whole-exome sequencing in combination with transcriptome profiling enables the description of the expressed protein coding mutanome.Genomic aberrations are identified by using at least 2 algorithms for bioinformatic analysis, known in the art. The prevalence of total mutations in the whole genome after application of the mutagen agents will confirm the higher mutation and/or CNV load in output ESCs or IPSCs.Qualitative and quantitative criteria will allow defining each cell population within genetic mosaicism in ESCs or IPSCs as described:Qualitative criteria include:- Identification of acquired novel molecular somatic alterations (mutations, CNVs or SNVs) defined regarding their presence in ESCs or IPSs genome after mutagenesis and their absence in ESCs or IPSCs without mutagenesis in similar cultured passages.- Classification of each novel mutations (i.e non-synonymous, nonsense, splice variant, CNVs, SNVs) and validation by their overlapping detection in cancer genome (from data base i.e. TCGA, ICGC, COSMIC) and present in pluripotent genes and embryonic pathways (according pluripotency genes i.e Plurinet gene).
Quantitative criteria such include: - The prevalence of these novel somatic mutations (with false discovery rate confidence value FDR < 0.05) and novel CNVs / SNVs (with FDR< 10%) in the whole genome is defined for each ESCs or IPSs.- The presence of validated mutation in at least > 3 different genes- The mutation rate of each novel and stable somatic mutations with an allelic frequency from at least from > 0.1%, or other percentages as seen above, up to 50% after clonal selection and expansion or regarding the number of passages (from 50X depth to100X depth and 80-98% of target exome coverage).- The expression of Pluripotency markers and a gene-expression based assay (PluriTest) with at least > 90% of expression rate compared to input ESCs or IPSCs before mutagenesis or genetic modification.- Expression of MHC I molecules at the cell surfaces (for instance as determined by FACS) being increased of at least 50 %, and generally up to 90 % as compared to a cell population expanded in the absence of HDACi, in particular VPA.
The present invention relates to vaccine composition that includes a population of pluripotent cells, as disclosed above and an agent that stimulates immune response and/or MHC I expression.In particular, such pluripotent cells are ESCs or IPSCs, preferably inactivated, and optionally mutated, as disclosed above.The agent that stimulates immune response may be an adjuvant (immunostimulant) as known in the art. It is preferably a HDACi (used at a dose range comprised between 0.2mM and 4mM). When such HDACi is used, another adjuvant may also be used.The invention also relates to a device (such as a syringe) containing such vaccine composition, that can be used for a simultaneous administration of the HDACi coumpound and the cell composition.Such vaccine composition can be used as a therapeutic vaccine against a stem cell cancer (cancer, the cells of which express neoantigens), for cure of the patient, or as a prophylactic vaccine, to prevent onset of such cancers, in particular in patients susceptible to these cancers.Predisposition genes are, for instance (see also Lindor et al, 2008 Journal of the National Cancer Institute Monographs, No. 38, Concise Handbook of Familial Cancer Susceptibility Syndromes, Second Edition):Breast / ovary: BRCA1, BRCA2, PALB2, RAD51 Lynch syndrome: MLH1, MSH2, MSH6, PMS2, EPCAMHereditary Papillary Renal Cell Carcinoma: FH, METCowden disease: PTEN, PIK3CAFanconi disease: FANCVon Hippel-Lindau disease: VHLMalicious melanoma: CDKN2A, MITF, BAP1, CDK4Endocrine Neoplasia: MEN1, RET, CDKN1BNeurofibromatosis:NF1, NF2, LZTR1, SMARCB1, SPRED1hereditary pheochromocytome paragangliome :SDH, TMEM127, MAX, EPAS1Familial adenomatous polyposis: APC, MUTYHRetinoblastoma: RB1Birt-hogg-dubé syndrome:FLCNBloom syndrome:BLMCarney syndrome:PRKAR1AGorlin syndrome:PTCH1Li-Fraumeni syndrome: TP53, CHEK2Nijmegen syndrome: NBNPeutz-Jeghers Syndrome:STK11Familial Juvenile Polyposis: BMPR1A, SMAD4Xeroderma pigmentosum: XPThis list is not limitative.In certain embodiment, cancer stem vaccine product comprise a mixture of cell lysate after lyophylisation, a mixture of enriched multi-cancer stem neoantigens, purified cancer stem neo-antigens, exosomes derived from ESCs or IPSCs, DNA, RNA Proteins or multiple peptides from engineered ESCs or IPSCs. These are the immunogenic agent as disclosed above, which are formulated in the presence of HDACi.In another embodiment, cancer stem cell vaccine product is mixed with supernatant GMP media from engineered irradiated ESCs or IPSCs used as an adjuvant effector.
In a preferred embodiment, the cells in this composition are inactivated (i.e. can not divide anymore).The composition of cells of the invention is susceptible to be obtained by any of the methods as disclosed above.
It is to be noted that the cells in this composition are heterogeneous in nature, when the mutagen has been used and hence differ from a pluripotent cell composition that has been cultured according to methods known in the art, and which is homogenous.When it has been cultured in the absence of a mutagen, the population of cell differs from a population of cells that has been cultured according to methods known in the art, as the presence of the agent maintaining expression of pluripotent genes and increasing MHC I presentation, in the culture medium, will lead to cells that have more of these MHC I molecules on their surface.As used herein the term "compound selected from a group which activates MHC expression and/or immune response" refers to compounds which are capable of stimulating immunogenicity. Such compound is called activator of MHC expression and/or immune response. The term "MHC" refers to major histocompatibility complex which is present on the cell surface to recognize foreign molecules, called antigens. MHC binds to antigens and present them to immune molecules such as lymphocytes T and B. The term "immune response" refers to immunological response of immune system to an antigen. By activating the immune response, the population of FoxP3 subpopulation and myeloid-derived suppressor cell (MDSC) are decreased and, in contrary the NK population is increased. In the context of the invention, the immune response against tumors comprises a cytotoxic T cell response against an antigen present in or on a cell of the tumor. In some embodiments, the cytotoxic T cell response is mediated by CD8+ T cells. Typically, in the context of the invention, the antigen which activates the MHC expression and/or immune response corresponds to the molecules present on the population of pluripotent cells as described above. The compound which activates the MCH expression and/or immune system is a neo-antigen. The term "neoantigen" or "neo-antigenic" means a class of antigens that arises from at least one mutation which alters the amino acid sequence of genome encoded proteins In the context of the invention, compounds are selected from the group consisting of: cytokines, histone deacetylase inhibitors, DNA methyltransferase inhibitors, and histonelysine N-methyltransferase enzyme inhibitors.In a particular embodiment, the activator of MHC expression and/or of immune response is a histone deacetylase inhibitor.As used herein, the term histone "histone deacetylase inhibitor" called also HDACi, refers to a class of compounds that interfere with the function of histone deacetylase. Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Typically, inhibitors of HDACs modulate transcription and induce cell growth arrest, differentiation and apoptosis. HDACis also enhance the cytotoxic effects of therapeutic agents used in cancer treatment, including radiation and chemotherapeutic drugs.In a particular embodiment, the histone deacetylase inhibitor is valproic acid (VPA).The term "valproic acid" refers to acid-2- propylpentanoic (C8H16O2), which has the following CAS number and formula 99-66-1 in the art:: The biological activities of valproic acid are multiple (Chateauvieux et al, J. Biomed. Biotechnol, 2010, pii: 479364. doi: 10.1155 / 2010/479364). Valproic acid affects the neurotransmitter GABA (Gamma Amino Butyrate) potentiating inhibitory activity. Several mechanisms of action are suggested. Valproic acid is particularly the GABA metabolism: inhibits degradation of GABA, GABA Transaminobutyratre (LAMP), acroissement of GABA synthesis, and modifies its turnover. In addition, valproic acid blocks certain ion channels, reduces arousal mediated by the N-Methyl- D-Aspartate, and blocks the activity of ion channels including Na+ and Ca 2+ (voltage- dependent L-type CACNA1 type C, D, N, and F).In the context of the invention, valproic acid is used as an immune-stimulant to boost immune response against cancers expressing pluripotent antigens shared with human embryonic stem cells (ESCs) or induced pluripotent stem cells (IPSCs).More particularly, VPA is used to stimulate and enhance the expression of MHC-I on cancer stem cell compartment, increasing the neo-antigen content in the CSC compartment. Higher expression of MHC I in ESCs and IPSCs and in CSCs allow to enhance the presentation of neo-antigens associated with MHC- I to APC/ Dendritic cells to induce THimmune response. Higher level of chemokines (CXCL9, CXCL10…) allow to enhance the recruitment of T cell into the tumor.The present invention relates to methods to increase the neo-antigen content in the CSC compartment expression of embryonic antigens in CSC and tumor cells through chromatin remodelling, as well as chemokines expression (CXCL9, CXCL10…) by expanding pluripotent cells in the presence of an HADCi such as VPA and/or 5 Azacytidine.In particular, when used for treating a patient in vivo, the present compositions and vaccines makes it possible to modify the tumor microenvironment and promote the recruitment of T cells into the tumor, so as to obtain a long term durable reduction of tumor volume.This is due to a synergistic effect of the cancer primed pluripotent cell vaccine and VPA co-administration, that is further improved when the HDACi is further administered to the patient, for a period of time (such as at least 15 days) after vaccine injection.The examples show that combined treatment by both cancer stem cell vaccine and VPA provide a superior anti-tumor response by increasing TILs with Th1/Th2 cellular immunity, decreasing FoxP3 TReg subpopulation, activating NK cells and decreasing the suppressive action of MDSC, while reversing the tumor immune suppression and decrease the TReg (in tumor and spleen) and recruiting T CD4+ and CD8+ lymphocytes into the tumor with a less proportion of T CD4 and CD8 expressing PD-1.
VPA may down regulate c-Myc expression level and potentially induce apoptosis and autophagy of cancer cells and CSCs. VPA may boost the adaptive immune response via autophagosome cross-presentation.A well other known action of VPA is the decrease of inflammation cytokines such as IL6, IL8, TNFa interleukin (IL)-1beta, IL-17 in the lymph nodes.
In a particular embodiment, the histone deacetylase inhibitor is suberoylanilide hydroxamic acid, also called Vorinostat (N-Hydroxy-N′-phenyloctanediamide) was the first histone deacetylase inhibitor approved by the U.S. Food and Drug Administration (FDA) on 2006 (Marchion DC et al 2004; Valente et al 2014).In a particular embodiment the histone deacetylase inhibitor is Panobinostat (LBH- 589) has received the FDA approval on 2015 and has the structure as described in Valente et al 2014.In a particular embodiment the histone deacetylase inhibitor is Givinostat (ITF2357) has been granted as an orphan drug in the European Union (Leoni et al 2005; Valente et al 2014).
In a particular embodiment the histone deacetylase inhibitor is Belinostat also called Beleodaq (PXD-101) has received the FDA approval on 2014 (Ja et al 2003; Valente et al 2014).In a particular embodiment the histone deacetylase inhibitor is Entinostat (as SNDX- 275 or MS-275). This molecule has the following chemical formula (C21H20N4O3) and has structure as described in Valente et al 2014.In a particular embodiment the histone deacetylase inhibitor is Mocetinostat (MGCD01030) having the following chemical formula (C23H20N6O) (Valente et al 2014).In a particular embodiment the histone deacetylase inhibitor is Practinostat (SB939) having the following chemical formula (C20H30N4O2) and the structure as described in Diermayr et al 2012.In a particular embodiment the histone deacetylase inhibitor is Chidamide (CS055/HBI-8000) having the following chemical formula (C22H19FN4O2).In a particular embodiment the histone deacetylase inhibitor is Quisinostat (JNJ- 26481585) having the following chemical formula (C21H26N6O2).In a particular embodiment the histone deacetylase inhibitor is Abexinostat (PCI24781) having the following chemical formula (C21H23N3O5) (Valente et al 2014).In a particular embodiment the histone deacetylase inhibitor is CHR-3996 having the following chemical formula (C20H19FN6O2) (Moffat D et al 2010; Banerji et al 2012).In a particular embodiment the histone deacetylase inhibitor is AR-42 having the following chemical formula (C18H20N2O3) (Lin et al 2012).In a particular embodiment, the activator of MHC expression is DNA methyltransferase inhibitors.As used herein, the term "DNA methyltransferase inhibitors" refer to compounds which are capable of interacting with DNA methyltransferase (DNMT) and inhibiting their activity. DNMT are the enzymes which catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.In a particular embodiment, the DNA methyltransferase inhibitor is azacytidine, also known as 5-aza-2-deoxycytidine having the following chemical formula (C8H12N4O5) and structure in the art (Kaminskas et al 2004; Estey et al 2013).In a particular embodiment, the DNA methyltransferase inhibitor is decitabine also known as 5-aza-2'-deoxycytidine, having the following formula (C8H12N4O4) (Kantarjian et al 2006).
In a particular embodiment, the activator of MHC expression and/or immune response is a histone-lysine N-methyltransferase enzyme inhibitor, or DNA methyltransferase inhibitor. As used herein, the term "histone-lysine N-methyltransferase enzyme inhibitor" refers to compounds which are capable of interacting with histone-lysine N-methyltransferase enzyme encoded by Enhancer of zeste homolog 1 (EZH1) and 2 (EZH2) gene that participates in DNA methylation. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine by using the cofactor S-adenosyl-L-methionine.In a particular embodiment, the histone-lysine N-methyltransferase enzyme inhibitor is 3-Deazaneplanocin A (DZNep, C-c3Ado). DZNep, C-c3Ado has the following chemical formula C12H14N4O3 and CAS number 102052-95-9 in the art.In a particular embodiment, the histone-lysine N-methyltransferase enzyme inhibitor is UNC1999 and an inactive analog compound. UNC1999 has the following chemical formula C33H43N7O2 and CAS number 1431612-23-5 in the art.In a particular embodiment, the histone-lysine N-methyltransferase enzyme inhibitor is UNC2400 and an inactive analog compound. UNC2400 has the following chemical formula C35H47N7O2 and CAS number 1433200-49-7 in the art.In a particular embodiment, the histone-lysine N-methyltransferase enzyme inhibitor is tazemetostat (EPZ6438, E7438). Tazemetostat has the following chemical formula C34H44N4O4 and CAS number 1403254-99-8 in the art.In a particular embodiment, the histone-lysine N-methyltransferase enzyme inhibitor is trifluoroacetate (EPZ011989). Trifluoroacetate has the following chemical formula CF3COONa and CAS number 2923-18-4 in the art.In a particular embodiment, the histone-lysine N-methyltransferase enzyme inhibitor is EPZ005687. EPZ005687 has the following chemical formula C32H37N5O3 and CAS number 1396772-26-1 in the art.In a particular embodiment, histone-lysine N-methyltransferase enzyme inhibitor is GSK343. GSK343 has the following chemical formula C31H39N7O2 and CAS number 1346704-33-3 in the art.In a particular embodiment, histone-lysine N-methyltransferase enzyme inhibitor is GSK126. GSK126 has the following chemical formula C31H38N6O2 and CAS number 1346574-57-9 in the art.In a particular embodiment, histone-lysine N-methyltransferase enzyme inhibitor is GSK2816126. GSK2816126 has the following chemical formula C31H38N6O2 and CAS number 1346574-57-9 in the art.
In a particular embodiment, histone-lysine N-methyltransferase enzyme inhibitor is ZLD1039. ZLD1039 has the following chemical formula C36H48N6O3 and CAS number 1826865-46-6 in the art.
It is also envisaged to use both a HDACi and a DNA methyltransferase inhibitor.Indeed, it has been shown that the combined use of VPA and 5-Azacytidine (an analog of the nucleoside cytidine which can be incorporated into DNA and RNA) leads to a synergetic effect on the re-expression of neo anti-embryonic antigens.
The HDACi is administered in a therapeutically efficient amount. For VPA, it may be from 10 to 15 mg/kg/day, up to 60 mg/kg/day. The plasma level of VPA should preferably be in the usually accepted therapeutic range (50 to 100 µg/mL).
In a further aspect, the method according to the invention is suitable to treat cancers expressing a large number of embryonic antigens which share the expression with human embryonic stem cells (hESC) or human induced Pluripotent Stem Cells (hiPSCs). (e.g. Embryonic Antigen-3 (SSEA3), SSEA4, TRA-1-60, TRA-1-81, Oct4, Sox2, Klf4, Nanog, Lin28…).
As used herein, the terms "cancers expressing human stems cells", are the cancers that are preferably targeted by the methods, vaccines and compositions herein disclosed, refer to cancer stem cells expressing a large number of embryonic antigens which share the expression with human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Typically, the cancer is selected from the group consisting of bladder carcinoma, breast carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal carcinoma, gastric sarcoma, glioma, lung carcinoma, lymphoma, acute and chronic lymphoid and myeloid leukemias, melanoma, multiple myeloma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, stomach carcinoma, kidney carcinoma, a head and neck tumor, and a solid tumor.As used herein the terms "administering" or "administration" refer to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., combined preparation) into the subject, such as by mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery and/or any other method of physical delivery described herein or known in the art. When a disease, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of the disease or symptoms thereof. When a disease or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease or symptoms thereof.In the preferred embodiment, the vaccine composition (pluripotent cells + agent stimulating MHC presentation) is injected subcutaneously. Injection may be simultaneous, sequential, separate, at the same injection point or at different injection points, in the same syringe, or in separate syringes…In a preferred embodiment, the follow-up treatment (administration of the compound that stimulates MHC I and/or immune system, such as an HDACi, in particular VPA) is administered by the oral route.A "therapeutically effective amount" is intended for a minimal amount of active agent which is necessary to impart therapeutic benefit to a subject. For example, a "therapeutically effective amount" to a subject is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. It will be understood that the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
In a particular embodiment, the method according to the invention comprises further one or more of radiation therapy, targeted therapy, immunotherapy, or chemotherapy. Typically, the physician could choose to administer the subject with i) a population of pluripotent cells and ii) a compound selected from a group which activates MHC expression and/or immune response, as a combined preparation with radiation therapy, targeted therapy, immunotherapy, or chemotherapy.
In some embodiments, the subject is administered with i) a population of pluripotent cells and ii) a compound selected from a group which activates MHC expression and/or immune response, as a combined preparation and a chemotherapeutic agent.The term "chemotherapeutic agent" refers to chemical compounds that are effective in inhibiting tumor growth. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaorarnide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estrarnustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimus tine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g. calicheamicin, especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl. 33:183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholinodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idanrbicin, marcellomycin, mitomycins, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomgrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophospharnide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pento statin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogennanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylarnine; trichothecenes (especially T-toxin, verracurin A, roridinA and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobromtol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g. paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and phannaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are antihormonal agents that act to regulate or inhibit honnone action on tumors such as antiestrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and phannaceutically acceptable salts, acids or derivatives of any of the above.
In some embodiments, the subject is administered with i) a population of pluripotent cells and ii) a compound selected from a group which activates MHC expression and/or immune response, as a combined preparation and a targeted cancer therapy.
Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. Targeted cancer therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or similar names. In some embodiments, the targeted therapy consists of administering the subject with a tyrosine kinase inhibitor. The term "tyrosine kinase inhibitor" refers to any of a variety of therapeutic agents or drugs that act as selective or non-selective inhibitors of receptor and/or non-receptor tyrosine kinases. Tyrosine kinase inhibitors and related compounds are well known in the art and described in U.S Patent Publication 2007/0254295, which is incorporated by reference herein in its entirety. It will be appreciated by one of skill in the art that a compound related to a tyrosine kinase inhibitor will recapitulate the effect of the tyrosine kinase inhibitor, e.g., the related compound will act on a different member of the tyrosine kinase signalling pathway to produce the same effect as would a tyrosine kinase inhibitor of that tyrosine kinase. Examples of tyrosine kinase inhibitors and related compounds suitable for use in methods of embodiments of the present invention include, but are not limited to, dasatinib (BMS-354825), PP2, BEZ235, saracatinib, gefitinib (Iressa), sunitinib (Sutent; SU11248), erlotinib (Tarceva; OSI-1774), lapatinib (GW572016; GW2016), canertinib (CI 1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), imatinib (Gleevec; STI571), leflunomide (SU101), vandetanib (Zactima; ZD6474), bevacizumab (avastin), MK-2206 (8-[4-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4- f][1,6]naphthyridin-3(2H)-one hydrochloride) derivatives thereof, analogs thereof, and combinations thereof. Additional tyrosine kinase inhibitors and related compounds suitable for use in the present invention are described in, for example, U.S Patent Publication 2007/0254295, U.S. Pat. Nos. 5,618,829, 5,639,757, 5,728,868, 5,804,396, 6,100,254, 6,127,374, 6,245,759, 6,306,874, 6,313,138, 6,316,444, 6,329,380, 6,344,459, 6,420,382, 6,479,512, 6,498,165, 6,544,988, 6,562,818, 6,586,423, 6,586,424, 6,740,665, 6,794,393, 6,875,767, 6,927,293, and 6,958,340, all of which are incorporated by reference herein in their entirety. In certain embodiments, the tyrosine kinase inhibitor is a small molecule kinase inhibitor that has been orally administered and that has been the subject of at least one Phase I clinical trial, more preferably at least one Phase II clinical, even more preferably at least one Phase III clinical trial, and most preferably approved by the FDA for at least one hematological or oncological indication. Examples of such inhibitors include, but are not limited to, Gefitinib, Erlotinib, Lapatinib, Canertinib, BMS-599626 (AC-480), Neratinib, KRN-633, CEP-11981, Imatinib, Nilotinib, Dasatinib, AZM-475271, CP-724714, TAK-165, Sunitinib, Vatalanib, CP-547632, Vandetanib, Bosutinib, Lestaurtinib, Tandutinib, Midostaurin, Enzastaurin, AEE-788, Pazopanib, Axitinib, Motasenib, OSI-930, Cediranib, KRN-951, Dovitinib, Seliciclib, SNS-032, PD-0332991, MKC-I (Ro-317453; R-440), Sorafenib, ABT-869, Brivanib (BMS-582664), SU-14813, Telatinib, SU-6668, (TSU-68), L- 21649, MLN-8054, AEW-541, and PD-0325901.
In some embodiments, the subject is administered with i) a population of pluripotent cells and ii) a compound selected from a group which activates MHC expression and/or immune response, as a combined preparation and an immune checkpoint inhibitor.As used herein, the term "immune checkpoint inhibitor" refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins. Checkpoint proteins regulate T-cell activation or function. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD1 with its ligands PDLl and PDL2 (Pardoll, Nature Reviews Cancer 12: 252-264, 2012). These proteins are responsible for co-stimulatory or inhibitory interactions of T-cell responses. Immune checkpoint proteins regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies. In some embodiments, the immune checkpoint inhibitor is an antibody selected from the group consisting of anti-CTLA4 antibodies (e.g. Ipilimumab), anti-PD1 antibodies (e.g. Nivolumab, Pembrolizumab), anti-PDL1 antibodies, anti-TIM3 antibodies, anti-LAG3 antibodies, anti- B7H3 antibodies, anti-B7H4 antibodies, anti-BTLA antibodies, and anti-B7H6 antibodies. Examples of anti-CTLA-4 antibodies are described in US Patent Nos: 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; 6,682,736; 6,984,720; and 7,605,238. One anti-CTLA-antibody is tremelimumab, (ticilimumab, CP-675,206). In some embodiments, the anti- CTLA-4 antibody is ipilimumab (also known as 10D1, MDX-D010) a fully human monoclonal IgG antibody that binds to CTLA-4. Another immune checkpoint protein is programmed cell death 1 (PD-1). Examples of PD-1 and PD-L1 blockers are described in US Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149, and PCT Published Patent Application Nos: WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699. In some embodiments, the PD-1 blockers include anti-PD-Ll antibodies. In certain other embodiments, the PD-1 blockers include anti-PD-1 antibodies and similar binding proteins such as nivolumab (MDX 1106, BMS 936558, ONO 4538), a fully human IgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-Ll and PD-L2; lambrolizumab (MK- 3475 or SCH 900475), a humanized monoclonal IgG4 antibody against PD-1; CT-011 a humanized antibody that binds PD-1 ; AMP-224 is a fusion protein of B7-DC; an antibody Fc portion; BMS-936559 (MDX- 1105-01) for PD-Ll (B7-H1) blockade. Other immune- checkpoint inhibitors include lymphocyte activation gene-3 (LAG-3) inhibitors, such as IMP321, a soluble Ig fusion protein (Brignone et al., 2007, J. Immunol. 179:4202-4211). Other immune-checkpoint inhibitors include B7 inhibitors, such as B7-H3 and B7-Hinhibitors. In particular, the anti-B7-H3 antibody MGA271 (Loo et al., 2012, Clin. Cancer Res. July 15 (18) 3834). Also included are TIM3 (T-cell immunoglobulin domain and mucin domain 3) inhibitors (Fourcade et al., 2010, J. Exp. Med. 207:2175-86 and Sakuishi et al., 2010, J. Exp. Med. 207:2187-94). In some embodiments, the immunotherapeutic treatment consists of an adoptive immunotherapy, as described by Nicholas P. Restifo, Mark E. Dudley and Steven A. Rosenberg ("Adoptive immunotherapy for cancer: harnessing the T cell response, Nature Reviews Immunology, Volume 12, April 2012). In adoptive immunotherapy, the patient’s circulating lymphocytes, or tumor-infiltrated lymphocytes, are isolated in vitro, activated by lymphokines such as IL-2 and readministered (Rosenberg et al., 1988; 1989). The activated lymphocytes are most preferably be the patient’s own cells that were earlier isolated from a blood sample and activated (or "expanded") in vitro.
In some embodiments, the subject is administered with i) a population of pluripotent cells and ii) a compound selected from a group which activates MHC expression and/or immune response, as a combined preparation and a radiotherapeutic agent.The term "radiotherapeutic agent" as used herein, is intended to refer to any radiotherapeutic agent known to one of skill in the art to be effective to treat or ameliorate cancer, without limitation. For instance, the radiotherapeutic agent can be an agent such as those administered in brachytherapy or radionuclide therapy. Such methods can optionally further comprise the administration of one or more additional cancer therapies, such as, but not limited to, chemotherapies, and/or another radiotherapy.
Pharmaceutical and vaccine compositions The compounds which activate MHC expression and/or immune response and the population of pluripotent cells as described above may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
"Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms. Typically, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The polypeptide (or nucleic acid encoding thereof) can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
More particularly, the population of pluripotent cells and the compound which activates MHC expression and/or immune response are formulated on a vaccine composition. Accordingly, the invention relates to a vaccine composition comprising i) a population of pluripotent cells and ii) a compound selected from a group which activates MHC expression and/or immune response.In a particular embodiment, the vaccine composition according to the invention comprising i) human embryonic stem cells and ii) acid valproic.In a particular embodiment, the vaccine composition according to the invention comprising i) induced pluripotent stem cells (iPSCs) expressing neo-antigens, in particular enhanced by mutagen agents or genetic modification and ii) valproic acid.The composition may also comprise 5 Azacytidine.Moreover, the vaccine composition of the present invention can be used in a subject suffering from a cancer as described above.
The vaccine composition according to the invention can be formulated with the physiological excipients set forth above in the same manner as in the immunogenic compositions. For instance, the pharmaceutically acceptable vehicles include, but are not limited to, phosphate buffered saline solutions, distilled water, emulsions such as an oil/water emulsions, various types of wetting agents sterile solutions and the like. Adjuvants such as muramyl peptides such as MDP, IL-12, aluminium phosphate, aluminium hydroxide, Alum and/or Montanide(R) can be used in the vaccines.The vaccine composition according to the invention can be administered subcutaneous (s.c), intradermal (i.d.), intramuscular (i.m.) or intravenous (i.v.) injection, oral administration and intranasal administration or inhalation. The administration of the vaccine is usually in a single dose. Alternatively, the administration of the vaccine of the invention is made a first time (initial vaccination), followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,93, 94, 95, 96, 97, 98, 99 or 100 recalls (subsequent administration), with the same populationof stem cells, the compound which stimulates the immune system or a combination of thereof and/or with a further one or more of radiation therapy, targeted therapy, immunotherapy, or chemotherapy.
The vaccine composition is also provided in a kit. The kit comprises the vaccine composition and an information leaflet providing instructions for immunization. The kit comprises also the all materials for the administration of the products.
The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.
FIGURES: Figure 1: Vaccination study with mESCs, hESC, miPSCs and 4T1 cells on breast tumor 4T1 model.Study design: Mice (n=5 per group) received to boosts of vaccine 7 and days with 105 irradiated cells; murine Embryonic Stem Cells (mESCs), murine induced Pluripotent Stem Cells (miPSCs), human Embryonic Stem Cells (hESCs) or 4T1 cells . After days 5x104 4T1 cells were injected into the mammary fat pad of the mice. Fiver mice were injected with 4T1-CSC (4T1 cells growth with additional cytokines such as TGFbeta and TNFalpha in order to generate CSC growing in the form of mammospheres) Figure 2 : Immune protection after vaccination.A; Quantification of CD4 positive tumor infiltrating lymphocytes (TIL) by flow cytometry. B; Quantification of CD25 positive regulatory T cells by flow cytometry within the CD4+ TIL. C; Quantification of PDregulatory T cells by flow cytometry within the CD8+ T cells regarding the group of mice. Figure 3: Vaccination study with hESC combined with VPA on 4T1 mice model. Study design : Mice (n=5 per group) received to boosts of vaccine 7 and 14 days with 1irradiated cells hESCs with or without VPA. After 14 days 5x104 4T1 cells were injected into the mammary fat pad of the mice. A; Tumor volumes for each group: 1/control (PBS), 2/vaccination with hESC 3/ vaccination with hESCs combine with VPA, 4/ mice receiving only VPA. B: tumors weight at 44 days. Figure 4: Immune protection after hESC vaccination and VPA : A; decrease of PD1 cell in the spleen within the CD4 and CD8 populations. B, increase CD4+ and CD8+ T cells in the tumors. C: increase of CD4+ and CD8+ T cells in the spleen Figure 5 : Quantification of the luciferase reporter gene by the IVIS-Spectrum system on lungs after dissection for each animal of the 4 groups (control, hESC, hESC+VPA, VPA).
Figure 6 : Expression of puripotent gene by real time PCR on 4T1 cells and 4T1 CSC (mammospheres) treated with 0.5 mM of VPA for 5 days. Figure 7: Expression of Oct4 in 4T1 treated with VPA and 5Aza by RT PCR and real time PCR. Figure 8: Detection by exome sequencing of genetic variants altering protein sequences of neoantignes in iPSC treated or not by ENU . Quantification of variants in ENU-treated iPSC and none treated-iPSCs. (NS= Non Synonymous, FS= frameshift, SG= Stop Gained). Figure 9 : schematic representation of a process according to the invention.
EXAMPLES: EXAMPLE 1 It was reported that fetal tissues can be used to immunize mice that are able to reject transplantable tumors including cancer of the skin, liver, and gastrointestinal tract. This response is explained by the fact that those tumor cells express a high number of oncofetal antigens. To date several human cancer vaccine trials have been set up in order to target embryonic antigens such as carcinoembryonic antigen (CEA) and alpha fetoprotein or cancer/testes antigens. Unfortunately, targeting one antigen alone was shown to be not efficient enough to generate strong antitumor immune responses to mediate tumor rejection because of rapid appearance of escape mutants and the general inefficiency of monovalent cancer vaccines. Recent interest in the potential of stem cells in regenerative medicine has made well-defined undifferentiated ESC lines widely available as well as undifferentiated iPSCs that are phenotypically and functionally similar to ESCs. In our study we hypothesized that undifferentiated stem cells could be used as a polyvalent vaccine to generate an immune response against a variety of embryonic antigens that are shared by tumor cells and CSC. We found, for the first time, that ESCs or iPSCs were able to induce immune and clinical responses against breast carcinoma. Surprisingly we found that the addition of valproic acid in the therapeutic regimen could induce higher immune and anti-tumoral responses in comparison to the use of ESCs or iPSCs alone. Material & Methods We have developed a metastatic 4T1 breast tumor model in BALB/c mice. To verify the embryonic ES-like markers in 4T1 murine TNBC breast cancer cell lines a meta-analysis was performed with the embryonic cell samples (D3 stem cell – GSE51782 annotated with Affymetrix plateform GPL16570) and with integration of different datasets: TNBC cell line 4T1 cultivated in vitro (GSE73296 annotated with Affymetrix plateform GPL6246), TNBC cell line 4T1 xenotransplanted in mouse model (GSE69006 annoted with Affymetrix plateform GPL6246) and mammary gland samples (GSE14202 annotated with plateform GLP339) (Padovani et al. 2009). For this 4T1 model it was shown by micro-array analysis that transplanted 4T1 in balb/c mice share 1304 different genes with murine ESCs including TRAP1A, TET1, TSLP, FAM169A, ETV5, MOXD1, PHLDA2, CRIP1, ADAMDEC1, NID1, EPCAM, H2-EA-PS, GPA33, IBSP, KANK3, MEST, MMP9, SPRY4, CLDN4, PRSS22, DDAH2, SPRY2, USP11, CTNNAL1, ZFP532, GRB10, CACNG7, ST14, CTH, RCN1, PECAM1, TMEFF1, PPP1R1A, GPR97, KIF2C, BRCA2, SLAIN1, CSRP2, DOCK6, HUNK, RAD51, ESYT3, SKP2, CCL24, SFRP1, HMGB2, ITM2A, ASPN, MSH2, SUGT1, ARHGAP8, ect. All these genes were thus found commonly upregulated in 4T1 and mESC , in comparison to normal murine mammary gland. It was also shown that xenotransplanted 4T1 highly expressed CSC markers such as CD44 compared to cells that were harvested in vitro (39% versus 0.27% of CD44highCD24low) (not shown).In the same manner a whole-genome expression profile analysis was performed on Triple Negative Breast Cancer (TNBC) from patients. To verify the embryonic ES-like markers in patients with TNBC a meta-analysis performed with embryonic cell samples and human breast samples was performed by merging sample data from different datasets: dataset GSE18864 comprising 84 breast cancer samples and annotated with Affymetrix plateform GPL570 (Silver et al. 2010), dataset GSE20437 comprising 42 samples of human normal breast and annotated with affymetrix platform GPL96 (Graham et al. 2010), dataset GSE23402 comprising 42 samples of human embryonic stem cells and induced pluripotent stem cells and annotated with Affymetrix plateform GPL570 (Guenther et al. 2010), dataset of Breast cancer cell lines (Maire et al. 2013) and dataset GSE36953 comprising cell culture samples of TNBC cell lines and annotated with Affymetrix plateform GPL570 (Yotsumoto et al. 2013). A supervised one-way ANOVA analyzed between the 3 grade groups of breast cancer identified 4288 significant genes which allowed to class majority of triple negative breast cancer TNBC grade III with samples of IPS and ES including CDC20, KRT81, NCAPG, MELK, DLGAP5, AURKA, ADAM8, CCNB1, RRM2, QPRT, SLAMF8, EZH2, CENPF, HN1, CENPA, SLC19A1, SLC39A4, CDK1, SEPHS1, GMDS, TUBB, SCRIB, DDX39A, YBX1, MKI67, TKT, WDR1, SKP2, ISG20, NRTN, SEC14L1, GAPDH, ILF2, PSMB2, DHTKD1, TPX2, CCNB2, IL27RA, NADK, H2AFX, MRPS18A, AURKA, MCM7, MCAM, NOP2, KIF23, JMJD4, YIPF3, CDH3, TALDO1, BID, C16orf59, HMMR, BIRC5, ZNF232, RANBP1, CDK1, SHMT2, KIF20A, EPHB4, SPAG5, PPARD, ORC6, TUBB4B, LYZ, TK1, PDXK, NAA10, BAG6, SF3B3, MARCKSL1, MCM3, PSRC1, NUSAP1, ect. All these genes were thus found commonly up regulated in TNBC tumors and hESCs compared to normal human mammary gland.
Results Result 1 Vaccination with xenogeneic embryonic stem cells generates a immunological and an anti-tumoral response against breast cancer.
We first investigated whether vaccination with irradiated murine ESCs (mESC), murine induced Pluripotent Stem Cells (murine iPSCs), human embryonic stem cells (hESCs) or 4T1 cells was effective against breast cancer in a syngeneic 4T1 mice model. This vaccination was followed by challenging the mice with two different types of 4T1 cells: the 4T1 cultured normally in DMEM 10% of SVF or 4T1 cells that were growth with additional cytokines such as TGFbeta and TNFalpha in order to generate Cancer Stem Cells (CSC) growing in the form of mammospheres. We discovered that in contrast to the non-vaccinated mice, the mice vaccinated with hESCs, mESCs, murine iPSCS and 4T1 generated consistent cellular immune responses against 4T1 carcinoma that was correlated with a significant reduction of breast tumor volume (p<0.05) (Figure 1). We found that tumors grew progressively in the PBS-control group whereas, strikingly, immunization with mESC, miPS or hESC resulted in a retardation of tumor growth, with statistically significant differences in the average tumor size in each group compared with PBS group (Figure 1). We observed a drastic inhibition of tumor growth when mice were challenged with CSC derived -4Tcompared to the mice challenged with 4T1 that were growth under normal condition showing that the vaccination with syngeneic mESC preferentially targets CSCs. To further study the cellular immune mechanism mediating the antitumor effect, we analyzed the phenotype of tumor infiltrating lymphocytes from different groups and quantified the CD4, CD8, CD25 and PD1 subpopulations. The anti-tumoral effect was correlated with 1/ an increase of CD4+ TIL that was significantly (p=0.0039) correlated with the tumor size (Figure 2A), 2/ a decrease of the percentage of CD25 positive cells that was inversely correlated with the tumor size (Figure 2B), 3/ a decrease of PD1 positive cells that was more pronounced in mice having better repose to the vaccine regimen (vaccination with hECS, 4T1 or mESC) (Figure 2C).
Result 2 Vaccination with xenogeneic embryonic stem cells in combination with valproic acid (VPA) generates a higher anti-tumoral response against breast cancer and inhibits metastasis development.
To evaluate the metastatic sites in the 4T1 breast models, the 4T1 cells were genetically modified so that they expressed both GFP and luciferase reporter protein (4T1Luc-GFP), enabling their tracking in vivo using bioluminescence imaging (Ivis spectrum) in deeper organs (spleen, lung, bone, liver). The experiment was carried out as previously described but using only irradiated hESCs as the vaccine; 5 mice per group received two boosts of vaccine and 14 days with 105 irradiated hESCs cells with or without VPA at the dose of 0.40 mM in drinking water. After 14 days 5x104 4T1Luc-GFP cells were injected into the mammary fat pad of the mice. We discovered that in contrast to the non-vaccinated mice, the mice vaccinated with hESCs combined with VPA generated a higher cellular immune responses against 4T1 carcinoma that was correlated with a significant reduction of breast tumor volume (p<0.05) (Figure 3A,) and reduction of the tumor weight (Figure 3B). The anti-tumoral response was correlated with a drastic decrease of PD-1 expression on both in CD4+T cells and CD8+T cells in the mice receiving hESC and VPA (Figure 4A). In addition the anti- tumoral response was correlated with a significant increase of the percentage of CD4+T and CD8+T cells within the tumor (Figure 4B) and within the spleen (Figure 4C) exclusively for the mice having received the combined treatment (hESC and VPA) compared to the control group (PBS). We also found that all mice had significantly reduced lung metastasis mice treated with hESCs vaccine and VPA (Figure 5). Taken together, these results show that xenogeneic embryonic stem-based vaccination (hESC) with VPA has the strongest efficacy compared to the use of hESC and VPA alone. These results show that xenogeneic embryonic stem-based vaccination could be an efficient treatment to reduce tumor relapse in breast carcinoma.
EXAMPLE 2 -Valproic acid modulates the expression of MHC class 1 and the expression of embryonic genes The major histocompatibility complex (MHC) is a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules that plays an essential for the acquired immune system. The main function of MHC molecules is to bind to new and foreign antigens and to display them on the cell surface for recognition by the appropriate T- cells: By interacting with CD4 molecules on surfaces of helper T cells, MHC class II mediates establishment of specific immunity called acquired immunity or adaptive immunity. By interacting with CD8 molecules on surfaces of cytotoxic T cells, MHC class I mediates destruction of infected or malignant host cells.Immune tolerance is an important means by which growing tumors, which have mutated proteins and altered antigen expression, prevent elimination by the host immune system. Tumor immune tolerance can be explain in part by the absent of β2-m on the cell surface and or the absence of MHC class I on tumor cell. It was shown that VPA is able to increase the expression of MHC class I on 4T1 cells at dose between 0.2 mM to 2 mM.The expression of MHC class I on 4T1 and 4T1 mammosphere (CSC induced by the treatment by TNFa and TGFb) increases by 2 to 3 fold after 24 hr to 72 hr of exposure with mM of VPA.In particular, it was shown that VPA is able to increase the expression of HLA ABC MHC class I on iPSCs (63% versus 92%) and the expression of pluripotent markers such as SSEAand Tra1-60 (55% versus 72%) at the dose of 0.5mM.Those markers were decreased after ENU exposure (60 days of treatment), and were restored when cells were treatment with 0.5 mM of VPA (28% to 92% of HLA ABC positive iPSCs- ENU and iPSCs respectively) and (48% to 69% of SSEA4/Tra-1-60 positive iPSCs-ENU and iPSCs respectively).HDAC inhibitors as VPA can selectively alter gene transcription, in part, by chromatin remodeling and by changes in the structure of proteins in transcription factor. It was studied whether VPA can modulate the expression of pluripotent gene in breast tumor cells. For this purpose we have treated 4T1 and 4T1 mammospheres (CSC induced by the treatment by TNFa and TGFb) with 1 mM to 2 mM of VPA. In all cases VPA have increased by 2 to 3 fold the expression of three different important transcriptional factors that are highly expressed in ESC or iPSC such as Oct 4, Sox2 and Nanog (Figure 6). Importantly, an important synergic effect of these transcriptional factors expression was shown when tumor cells were treated with the combination of VPA and 5-Azacytidine (5aza) when used at doses that inhibits DNA methyltransferase, causing hypomethylation of DNA. In particular a 7 fold increase of oct-transcript was shown when 4T1 cells were treated with VPA and 5aza (Figure 7 A and B).
EXAMPLE 3 - Inducing DNA damage and DNA repair errors by genomic instability in iPSCs exposed to mutagens drug such as N-ethyl-N-nitrosourea (ENU) Ethyl-N-Nitrosurea (ENU) is a mutagenic alkylating agent which creates base transversions but also single point mutations and double strand DNA breaks (DSB).
It was possible to confirm that ENU allows DNA damage in iPSC.The amount of phosphorylated gamma-H2AX attracted to the sites of DSB present in the cells was evaluated. In this experiment, iPSC were detached from stromal cultures by the use of collagenase and treated in vitro with ENU at indicated concentrations (50 µg/ml) and times, followed by Western blot analyses using an anti-phospho-gamma H2AX antibody. An increase of gamma-H2AX levels seen as early time points as 2 minutes-10 minutes was shown, followed by return to basal levels.A protocol was designed, to induce genomic instability in iPSC by a sequential treatment of IPSC with ENU in order to accumulate DNA repair errors during extensive proliferation. Cells were treated for 60 days with daily medium changes with daily addition of ENU at a concentration of 10 µg/ml. VPA was added during culture.At day + 61, iPSCs are evaluated the genomic consequence of mutagenesis procedure in iPSC by Karyotype, and RNA sequencing, CGH arrays, exome sequencing, WGS. Genomic alterations accumulated in cultured iPSC are compared to iPSC not treated with ENU.After ENU exposition, mutated iPSC were maintained and expanded in culture with VPA. CGH arrays and exome sequencing are performed sequentially at different passages to confirm the genocopy of the somatic mutation prevalence in ENU-iPSC during their expansion. Phenotype of iPSCs is performed by assessing pluripotency Pluritest and expression of Oct4, Sox2, Nanog, Tra-1 60, SSEA4. We found that replication rate and population doubling are similar to iPSC without ENU exposition.iPSC were treated with 10 µg/ml of ENU and performed a exome sequencing for the detection of mutated neo antigens. 48 alterations in ENU treated-iPSC where found compared to 8 alterations in iPSCs without ENU (Figure 8). These loci were merged with cBioPortal program (http://www.cbioportal.org) allowing access to cancer genomics data sets from human tumor samples from different cancer studies. Using cBioPortal program it was shown that more than 10 to 75% of these alterations were found also deregulated in carcinoma (pancreas, lung prostate…). For all exome sequencing we estimate the depth of coverage of to 400 reads for all mutations that can be detected in ENU-treated iPSC.
EXAMPLE 4 - Haploinsufficiency for BRCA1 leads to DNA repair alteration and genomic instability with CNVs accumulation in iPSC during culture. Alteration of BRCA1/2 is involved in Hereditary Breast and Ovarian Cancer (HBOC) syndrome. BReast CAncer1 (BRCA1) is a tumor-suppressor gene and plays a pivotal role in the maintenance of genomic stability by controlling DNA repair in homologous recombination, double-strand break repair, S-phase and G2/M, spindle checkpoints, and in centrosomal regulation.A fibroblast harboring a deletion of exon 17 in BRCA1 was reprogrammed with Sendai viruses containing Oct3/4, Sox2, Klf4, and cMyc (CytoTune®-iPS Sendai Reprogramming Kit, Life technologies). Cells were cultured in human pluripotent stem cell medium (hPSC medium) based on DMEM/F12 supplemented with 20% Knock Out Serum Replacer, 1 mM L-glutamine, 1% penicillin/streptomycin, 100 μM 2-mercaptoethanol (Life technologies) and 12.5 ng/ml basic FGF (Miltenyi Biotech). At day 26, fully reprogrammed colonies were manually picked based on their morphology and pluripotency markers by FACS analysis, Q RT-PCR of Nanog, Oct4 Sox2, teratoma formation in NOD-SCID mice and Pluritest. Karyotype was normal.The levels and activity of the DNA Damage Response (DDR) in normal (WT) and BRCA+/- iPSCs were compared. Gamma H2AX foci was determined by immunofluorescence in proliferating iPSC after irradiation or ENU exposition. IPSC BRCA1+/- exhibited significantly higher levels of phosphorylated ATM/ATR substrates as well as gamma H2AX recruitment to DNA compared with normal WT-iPSC, indicating that proliferating IPSC BRCA1+/- suffer increased DNA damage compared with WT-IPSC.Since iPSC BRCA1+/- displayed increased levels of DDR at early passages, it was examined whether this might be associated with accumulation of genomic alterations during iterative passages and proliferation.CGH array in proliferating pluripotent stem cells was analyzed after prolonged passaging of iPSC in medium supplemented with HDACi (VPA). For this purpose, Agilent CGHarray experiments were performed on DNA from IPSCs samples with the Roche-Nimbelgen aCGH platform. Signal extraction and genomic intervals were identified with Agilent cytogenomics and Nexus Roche-Nimbelgen softwares on HG18 of human genome. Gene loci were converted on HG19 coordinates with Roche-Nimbelgen annotation files (Genes_July_2010_hg19, Roche-Nimbelgen website). European Copy number variations (CNV) polymorphism were eliminated from experiments with scandb database (Gamazon et al. 2010). Array CGH CNV ratios were drawn as heatmap with MEV version 4.9.0 standalone software (red: gain, green: loss and dark zero) (Saeed et al. 2003). Gene loci found affected in cell of origin were subtracted from gene loci affected in respective IPSCs sample. Resulting filtered CNV specific of each iPSCs were merged COSMIC census database (Futreal et al. 2004). Genomic Circosplot on HG19 was performed with cancer genes found affected in each IPSCs after filtration. This genomic draw was performed with OmicCircos R-package in R environment version 3.0.2 (Hu et al. 2014).It was shown that culture of iPSC BRCA1+/- (>100 days) leads at late passages to an accumulation of genomic abnormalities concomitant with increased genomic instability without ENU exposition. Karyotype at late passage is normal. Agilent aCGH experiments were performed on DNA extract from iPSC cells and from their respective cell of origin. Genomic mapping of intervals affected during these pluripotency inductions showed that BRCA1+/- IPSC was affected by an important number of gene loci affected as compared to WT one. After CNV European polymorphism filtration on WT iPSC only 58 gene loci were still found affected (polymorphism represent 1.69% of the total loci affected), similarly on BRCA1-/+ iPSC 5273 gene loci were still found affected after polymorphism filtration. Majority of gene loci affected in BRCA1+/- iPSC concerned gain of DNA.Among these gene loci affected by genomic instability some of them are known as driver cancer gene in census COSMIC database. WT iPSCs showed only one cancer gene locus affected in aCGH (CDK4). BRCA1-/+ IPSC is affected by alterations concerning 131 cancer gene loci and among them 11 genes are known to be affected in breast cancer: MSH2, SMARCD1, TBX3, CDH1, TP53, ERBB2, CDK12, BRCA1, PPP2R1A, AKT2, EP300. These alterations were found particularly over-represented on small chromosomes 19 and 17: chromosome 17 which is the chromosome of BRCA1 gene loci.All together the majority of iPSC BRCA1+/- exhibited a higher amount of indels (deletion or amplification) compared in WT-IPSC. A rate of 8% of CNVs on 5273 genes was identify and validated. Bioinformatic analysis revealed the expression of 131 genes identified in cosmic data base to be involved in cancer development, essentially in leukemias, epithelial tumors and in mesenchymal tumor cells. Some altered genes are similarly observed in breast and ovarian cancers.Replication rate, pluripotency gene (Pluritest, cell surface markers) and MHC I are maintained and stable during all time of culture in presence of VPA.In conclusion deletion or inactivation of DNA repair related genes such as BRCA-1 allow to induce genomic instability leading to generate multiple CNV, indels and mutations associated to MHC I.
EXAMPLE 5 - N-ethyl-N-nitrosourea (ENU) increases the load of mutated neo antigens in CML- iPSCs Characterization of iPSC generated from leukemic blood cells of a patient with Philadelphiapositive chronic myeloid leukemia (CML). iPSC were generated by the use of Sendaï-virus mediated transfer of pluripotency genes Oct4, c-Myc, Klf4 and Sox2. Cells with pluripotent iPSC morphology were amplified and characterized using cell surface pluripotrency markers (Tra-1-60 and SSEA4) as well as by their ability to generated teratoma after intramuscular injection into NSG mice. These iPSC harbored Philadelphia chromosome characteristics of CML. CML iPSc were exposed to ENU during 60 days. Cell derivatives blast colonies from CML-IPS treated by ENU were compared to IPSC not treated with ENU.DNA of CML iPSC was analyzed by CGH array Several genomic aberrations were observed in blast-colonies derived drom ENU-treated iPSC with detection of loss of heterogeneity among genomic aberrations selected by ENU pressure on CML IPSC (CB32 These included copy number variations CNVs which comprised 332 gene loci). After filtration on European Caucasian genomic polymorphism database 255 gene loci were still present in these genomic aberrations. Majority of the genomic abnormalities included loss of genomic DNA (71%) with loss of heterozygosity (23%). Matching these genomic aberrations with transcription factor database, cancer gene database and pluripotency gene database allowed to observe that these important deregulated actors are principally affected on chromosomes 7, 8, 15, Y, and X. A Circosplot also allowed to determine that majority of these abnormalities implicated transcription factors such as MESP implicated in mesodermal cell migration and IKZF1. Some pluripotency genes were affected as well as some cancer genes like IDH2, NCOA2, IKZF1, BLM which have been already described to be involved in Ph1-positive leukemias, suggesting the relevance of the abnormalities generated by ENU-induced mutagenesis.This analysis shows that several gene alterations such as gains and losses and several of the abnormalities identified were found to be cancer genes identified in Cosmic database.The comparison of the abnormalities identified in the ENU-iPSC allowed to reproduce the aggressive acute leukemia phase abnormalities already identified in CML patients in acute leukemia phase, suggesting that ENU-treated CML iPSC is a unique tool to reproduce in vitro these genomic abnormalities in this specific cancer.
Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.
Claims (9)
1. A medicament comprising a combination of (i) a histone deacetylase inhibitor (HDACi) and (ii) a vaccine composition containing a population of pluripotent cells that have been inactivated for use in simultaneous, separate or sequential administration, for therapeutic or prophylactic treatment cancer in a subject.
2. The medicament according to claim 1, wherein the subject is a human.
3. The medicament according to claim 1, further comprising an HDACi, for administration at a period of time after the administration of the vaccine composition.
4. The medicament according to any one of claims 1 to 3, wherein the population of pluripotent cells has been obtained by: a. expanding pluripotent cells, in the presence of such conditions as to maintain the pluripotent ability of the cells, in the presence of an agent that induces MHC-I presentation of antigens in said population during the expansion step b. exposing the expanded cells to an inactivating agent that will inactivate the cells, while maintaining the cell envelope integrity c. recovering and conditioning the expanded inactivated cells.
5. The medicament according to claim 4, wherein the agent that induces MHC-I presentation of antigens is selected from the group consisting of cytokines, histone deacetylase inhibitors, DNA methyltransferase inhibitors, and histone-lysine N-methyltransferase enzyme inhibitors.
6. The medicament according to any one of claims 1 to 5, wherein cells of the population express an antigen of interest also expressed by the cancer cells of the patient, and in particular a neo-antigen.
7. The medicament according to any one of claims 1 to 6, wherein the cancer is selected from the group consisting of bladder carcinoma, breast carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal carcinoma, gastric sarcoma, glioma, lung carcinoma, lymphoma, acute and chronic lymphoid and myeloid leukemias, melanoma, multiple myeloma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, stomach carcinoma, kidney carcinoma, a head and neck tumor, and a solid tumor. 263224/3
8. A cancer vaccine composition comprising: a. a population of inactivated pluripotent cells and b. a histone deacetylase inhibitor.
9. The vaccine composition of claim 8, wherein the pluripotent cells contain mutagenized pluripotent cells.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16305607 | 2016-05-25 | ||
PCT/EP2017/062604 WO2017202949A1 (en) | 2016-05-25 | 2017-05-24 | Methods and compositions for treating cancers |
Publications (3)
Publication Number | Publication Date |
---|---|
IL263224A IL263224A (en) | 2018-12-31 |
IL263224B1 true IL263224B1 (en) | 2023-11-01 |
IL263224B2 IL263224B2 (en) | 2024-03-01 |
Family
ID=56131478
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL305882A IL305882A (en) | 2016-05-25 | 2017-05-24 | Methods and compositions for treating cancers |
IL263224A IL263224B2 (en) | 2016-05-25 | 2017-05-24 | Use of a histone deacetylase inhibitor and a population of inactivated pluripotent cells for treating cancer |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL305882A IL305882A (en) | 2016-05-25 | 2017-05-24 | Methods and compositions for treating cancers |
Country Status (11)
Country | Link |
---|---|
US (2) | US11458194B2 (en) |
EP (1) | EP3463433A1 (en) |
JP (2) | JP2019516754A (en) |
KR (3) | KR102677451B1 (en) |
CN (2) | CN109689089A (en) |
AU (2) | AU2017270234B2 (en) |
BR (1) | BR112018074192A8 (en) |
CA (1) | CA3025057A1 (en) |
IL (2) | IL305882A (en) |
RU (1) | RU2741786C2 (en) |
WO (1) | WO2017202949A1 (en) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10704021B2 (en) | 2012-03-15 | 2020-07-07 | Flodesign Sonics, Inc. | Acoustic perfusion devices |
US9725710B2 (en) | 2014-01-08 | 2017-08-08 | Flodesign Sonics, Inc. | Acoustophoresis device with dual acoustophoretic chamber |
US11377651B2 (en) | 2016-10-19 | 2022-07-05 | Flodesign Sonics, Inc. | Cell therapy processes utilizing acoustophoresis |
US11708572B2 (en) | 2015-04-29 | 2023-07-25 | Flodesign Sonics, Inc. | Acoustic cell separation techniques and processes |
US11214789B2 (en) | 2016-05-03 | 2022-01-04 | Flodesign Sonics, Inc. | Concentration and washing of particles with acoustics |
US11679148B2 (en) | 2017-11-24 | 2023-06-20 | Institut National De La Santé Et De La Recherche Médicale (Inserm) | Methods and compositions for treating cancers |
AU2018385759B2 (en) | 2017-12-14 | 2021-10-21 | Flodesign Sonics, Inc. | Acoustic transducer driver and controller |
MX2020006944A (en) | 2018-01-02 | 2020-11-09 | Khloris Biosciences Inc | Ipsc-based vaccine as a prophylactic and therapeutic treatment for cancer. |
WO2019140296A1 (en) * | 2018-01-12 | 2019-07-18 | Viracta Therapeutics, Inc. | Epigenetic modifiers for use in cellular immunotherapy |
CN112703011A (en) * | 2018-08-06 | 2021-04-23 | 国家医疗保健研究所 | Methods and compositions for treating cancer |
US20220154219A1 (en) * | 2019-03-22 | 2022-05-19 | The Johns Hopkins University | Gene delivery particles to induce tumor-derived antigen presenting cells |
WO2020232373A1 (en) * | 2019-05-15 | 2020-11-19 | Board Of Regents, The University Of Texas System | Crispr methods for treating cancers |
JP7352937B2 (en) * | 2019-07-19 | 2023-09-29 | 公立大学法人福島県立医科大学 | Differential marker gene set, method and kit for differentiating or classifying breast cancer subtypes |
CN111358777A (en) * | 2020-02-24 | 2020-07-03 | 军事科学院军事医学研究院环境医学与作业医学研究所 | Method for improving mitochondrial function of peripheral blood mononuclear cells and application |
CN112603995B (en) * | 2020-12-30 | 2022-03-18 | 四川省肿瘤医院 | CAFs-targeted tumor cell vaccine, preparation method and application thereof |
JP2024511657A (en) * | 2021-03-31 | 2024-03-14 | セレロン・セラピューティクス・リミテッド | vaccine adjuvant |
CA3214527A1 (en) * | 2021-04-05 | 2022-10-13 | Doo-Young Jung | Combined therapy of 4'-thio-5-aza-2'-deoxycytidine and venetoclax |
WO2023159124A2 (en) * | 2022-02-17 | 2023-08-24 | Memorial Sloan-Kettering Cancer Center | Methods for overcoming tazemetostat-resistance in cancer patients |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130136722A1 (en) * | 2011-11-11 | 2013-05-30 | The Board Of Trustees Of The University Of Illinois | Methods of Ex Vivo Expansion of Blood Progenitor Cells, and Generation of Composite Grafts |
Family Cites Families (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL8200523A (en) | 1982-02-11 | 1983-09-01 | Univ Leiden | METHOD FOR TRANSFORMING IN VITRO PLANT PROTOPLASTS WITH PLASMIDE DNA. |
US4806476A (en) | 1983-09-08 | 1989-02-21 | Lovelace Medical Foundation | Efficient cell fusion process |
US5071773A (en) | 1986-10-24 | 1991-12-10 | The Salk Institute For Biological Studies | Hormone receptor-related bioassays |
JP2740320B2 (en) | 1988-08-04 | 1998-04-15 | アムラド・コーポレイション・リミテッド | In vitro propagation of embryonic stem cells |
US5240840A (en) | 1991-04-05 | 1993-08-31 | Regents Of The University Of Michigan | Dna superfragment cloning |
JP3314241B2 (en) | 1992-04-06 | 2002-08-12 | ヤマハ発動機株式会社 | Exhaust gas purification device for motorcycle engine |
US5453357A (en) | 1992-10-08 | 1995-09-26 | Vanderbilt University | Pluripotential embryonic stem cells and methods of making same |
US5690926A (en) | 1992-10-08 | 1997-11-25 | Vanderbilt University | Pluripotential embryonic cells and methods of making same |
US5618829A (en) | 1993-01-28 | 1997-04-08 | Mitsubishi Chemical Corporation | Tyrosine kinase inhibitors and benzoylacrylamide derivatives |
ATE361759T1 (en) | 1993-07-15 | 2007-06-15 | Cancer Res Campaign Tech | COMPOUNDS THAT CAN BE USED FOR PRODUCING PROTEIN TYROSINE KINASE INHIBITOR PRODRUGS |
US5804396A (en) | 1994-10-12 | 1998-09-08 | Sugen, Inc. | Assay for agents active in proliferative disorders |
US5914268A (en) | 1994-11-21 | 1999-06-22 | National Jewish Center For Immunology & Respiratory Medicine | Embryonic cell populations and methods to isolate such populations |
US5843780A (en) | 1995-01-20 | 1998-12-01 | Wisconsin Alumni Research Foundation | Primate embryonic stem cells |
US5639757A (en) | 1995-05-23 | 1997-06-17 | Pfizer Inc. | 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors |
US5855887A (en) | 1995-07-25 | 1999-01-05 | The Regents Of The University Of California | Blockade of lymphocyte down-regulation associated with CTLA-4 signaling |
US6051227A (en) | 1995-07-25 | 2000-04-18 | The Regents Of The University Of California, Office Of Technology Transfer | Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling |
US5811097A (en) | 1995-07-25 | 1998-09-22 | The Regents Of The University Of California | Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling |
DK0892789T4 (en) | 1996-04-12 | 2010-04-06 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
US6207157B1 (en) | 1996-04-23 | 2001-03-27 | The United States Of America As Represented By The Department Of Health And Human Services | Conjugate vaccine for nontypeable Haemophilus influenzae |
US6331406B1 (en) | 1997-03-31 | 2001-12-18 | The John Hopkins University School Of Medicine | Human enbryonic germ cell and methods of use |
US6090622A (en) | 1997-03-31 | 2000-07-18 | The Johns Hopkins School Of Medicine | Human embryonic pluripotent germ cells |
ZA986732B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
US6100254A (en) | 1997-10-10 | 2000-08-08 | Board Of Regents, The University Of Texas System | Inhibitors of protein tyrosine kinases |
WO1999020741A1 (en) | 1997-10-23 | 1999-04-29 | Geron Corporation | Methods and materials for the growth of primate-derived primordial stem cells |
US6667176B1 (en) | 2000-01-11 | 2003-12-23 | Geron Corporation | cDNA libraries reflecting gene expression during growth and differentiation of human pluripotent stem cells |
EE05627B1 (en) | 1998-12-23 | 2013-02-15 | Pfizer Inc. | Human monoclonal antibodies to CTLA-4 |
US6740665B1 (en) | 1999-02-10 | 2004-05-25 | Ramachandran Murali | Tyrosine kinase inhibitors and methods of using the same |
US6245759B1 (en) | 1999-03-11 | 2001-06-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
EP1194152A4 (en) | 1999-06-30 | 2002-11-06 | Merck & Co Inc | Src kinase inhibitor compounds |
CA2383546A1 (en) | 1999-06-30 | 2001-01-04 | William H. Parsons | Src kinase inhibitor compounds |
EP1206260A4 (en) | 1999-06-30 | 2002-10-30 | Merck & Co Inc | Src kinase inhibitor compounds |
US7605238B2 (en) | 1999-08-24 | 2009-10-20 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
CA2381770C (en) | 1999-08-24 | 2007-08-07 | Medarex, Inc. | Human ctla-4 antibodies and their uses |
PL355639A1 (en) | 1999-09-10 | 2004-05-04 | Merck & Co, Inc. | Tyrosine kinase inhibitors |
US6794393B1 (en) | 1999-10-19 | 2004-09-21 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
AU778042B2 (en) | 1999-10-19 | 2004-11-11 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
CA2387351C (en) | 1999-10-19 | 2009-09-08 | Merck & Co., Inc. | Indole derivatives as tyrosine kinase inhibitors |
US6420382B2 (en) | 2000-02-25 | 2002-07-16 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
US6313138B1 (en) | 2000-02-25 | 2001-11-06 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
NL1017973C2 (en) | 2000-05-10 | 2002-11-08 | Tristem Trading Cyprus Ltd | Design. |
US6921632B2 (en) | 2000-08-30 | 2005-07-26 | Maria Biotech Co., Ltd. | Human embryonic stem cells derived from frozen-thawed embryo |
EP1403366B1 (en) | 2001-05-31 | 2015-05-27 | Shinya Yamanaka | Genes with es cell-specific expression |
CA2450562A1 (en) | 2001-06-22 | 2003-01-03 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
WO2003011836A1 (en) | 2001-08-01 | 2003-02-13 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
WO2003020276A1 (en) | 2001-08-30 | 2003-03-13 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
EP1456652A4 (en) | 2001-11-13 | 2005-11-02 | Dana Farber Cancer Inst Inc | Agents that modulate immune cell activation and methods of use thereof |
JP4511943B2 (en) | 2002-12-23 | 2010-07-28 | ワイス エルエルシー | Antibody against PD-1 and use thereof |
ES2398239T3 (en) | 2003-11-10 | 2013-03-14 | The Scripps Research Institute | Compositions and procedures to induce cell dedifferentiation |
PL2439273T3 (en) | 2005-05-09 | 2019-08-30 | Ono Pharmaceutical Co., Ltd. | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
CN104356236B (en) | 2005-07-01 | 2020-07-03 | E.R.施贵宝&圣斯有限责任公司 | Human monoclonal antibodies to programmed death ligand 1(PD-L1) |
US8129187B2 (en) | 2005-12-13 | 2012-03-06 | Kyoto University | Somatic cell reprogramming by retroviral vectors encoding Oct3/4. Klf4, c-Myc and Sox2 |
US8278104B2 (en) | 2005-12-13 | 2012-10-02 | Kyoto University | Induced pluripotent stem cells produced with Oct3/4, Klf4 and Sox2 |
US7908091B2 (en) | 2006-03-17 | 2011-03-15 | Prometheus Laboratories Inc. | Methods of predicting and monitoring tyrosine kinase inhibitor therapy |
CA2691357C (en) | 2007-06-18 | 2014-09-23 | N.V. Organon | Antibodies to human programmed death receptor pd-1 |
WO2009114335A2 (en) | 2008-03-12 | 2009-09-17 | Merck & Co., Inc. | Pd-1 binding proteins |
SG10201400329YA (en) | 2008-05-02 | 2014-05-29 | Univ Kyoto | Method of nuclear reprogramming |
CA2998281C (en) | 2008-09-26 | 2022-08-16 | Dana-Farber Cancer Institute, Inc. | Human anti-pd-1 antobodies and uses therefor |
EP4169951A1 (en) | 2008-12-09 | 2023-04-26 | F. Hoffmann-La Roche AG | Anti-pd-l1 antibodies and their use to enhance t-cell function |
JP5844159B2 (en) | 2009-02-09 | 2016-01-13 | ユニヴェルシテ デクス−マルセイユUniversite D’Aix−Marseille | PD-1 antibody and PD-L1 antibody and use thereof |
JP2013512251A (en) | 2009-11-24 | 2013-04-11 | アンプリミューン、インコーポレーテッド | Simultaneous inhibition of PD-L1 / PD-L2 |
WO2011082400A2 (en) | 2010-01-04 | 2011-07-07 | President And Fellows Of Harvard College | Modulators of immunoinhibitory receptor pd-1, and methods of use thereof |
WO2011159877A2 (en) | 2010-06-18 | 2011-12-22 | The Brigham And Women's Hospital, Inc. | Bi-specific antibodies against tim-3 and pd-1 for immunotherapy in chronic immune conditions |
US8907053B2 (en) | 2010-06-25 | 2014-12-09 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
JP5888753B2 (en) | 2010-11-04 | 2016-03-22 | 国立大学法人京都大学 | Efficient method for establishing induced pluripotent stem cells |
US9534206B2 (en) * | 2010-12-16 | 2017-01-03 | General Electric Company | Cell carrier, associated methods for making cell carrier and culturing cells using the same |
US8697359B1 (en) | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
-
2017
- 2017-05-24 RU RU2018141200A patent/RU2741786C2/en active
- 2017-05-24 AU AU2017270234A patent/AU2017270234B2/en active Active
- 2017-05-24 CN CN201780045481.XA patent/CN109689089A/en active Pending
- 2017-05-24 CN CN202211701185.XA patent/CN116376812A/en active Pending
- 2017-05-24 IL IL305882A patent/IL305882A/en unknown
- 2017-05-24 IL IL263224A patent/IL263224B2/en unknown
- 2017-05-24 US US16/303,705 patent/US11458194B2/en active Active
- 2017-05-24 WO PCT/EP2017/062604 patent/WO2017202949A1/en unknown
- 2017-05-24 KR KR1020227044304A patent/KR102677451B1/en active IP Right Grant
- 2017-05-24 BR BR112018074192A patent/BR112018074192A8/en not_active Application Discontinuation
- 2017-05-24 CA CA3025057A patent/CA3025057A1/en active Pending
- 2017-05-24 KR KR1020187037459A patent/KR20190032295A/en not_active IP Right Cessation
- 2017-05-24 JP JP2018561512A patent/JP2019516754A/en active Pending
- 2017-05-24 KR KR1020247020115A patent/KR20240103039A/en active Search and Examination
- 2017-05-24 EP EP17726274.8A patent/EP3463433A1/en active Pending
-
2022
- 2022-07-07 JP JP2022110028A patent/JP2022133444A/en active Pending
- 2022-07-28 US US17/815,586 patent/US20220370582A1/en active Pending
-
2024
- 2024-01-30 AU AU2024200549A patent/AU2024200549A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130136722A1 (en) * | 2011-11-11 | 2013-05-30 | The Board Of Trustees Of The University Of Illinois | Methods of Ex Vivo Expansion of Blood Progenitor Cells, and Generation of Composite Grafts |
Non-Patent Citations (3)
Title |
---|
BARTLETT DL, ET AL., ONCOLYTIC VIRUSES AS THERAPEUTIC CANCER VACCINES, 11 September 2013 (2013-09-11) * |
BRIDLE BW, ET AL., " HDAC INHIBITION SUPPRESSES PRIMARY IMMUNE RESPONSES, ENHANCES SECONDARY IMMUNE RESPONSES, AND ABROGATES AUTOIMMUNITY DURING TUMOR IMMUNOTHERAPY.", 1 April 2013 (2013-04-01) * |
DEBEB BG., ET AL., HISTONE DEACETYLASE INHIBITORS STIMULATE DEDIFFERENTIATION OF HUMAN BREAST CANCER CELLS THROUGH WNT/??CATENIN SIGNALING., 7 September 2012 (2012-09-07) * |
Also Published As
Publication number | Publication date |
---|---|
EP3463433A1 (en) | 2019-04-10 |
AU2024200549A1 (en) | 2024-02-15 |
US20220370582A1 (en) | 2022-11-24 |
KR102677451B1 (en) | 2024-06-24 |
BR112018074192A8 (en) | 2022-11-08 |
IL263224B2 (en) | 2024-03-01 |
WO2017202949A1 (en) | 2017-11-30 |
AU2017270234A1 (en) | 2019-01-17 |
IL263224A (en) | 2018-12-31 |
BR112018074192A2 (en) | 2019-08-13 |
KR20190032295A (en) | 2019-03-27 |
CN116376812A (en) | 2023-07-04 |
RU2741786C2 (en) | 2021-01-28 |
RU2018141200A3 (en) | 2020-07-29 |
RU2018141200A (en) | 2020-06-25 |
CA3025057A1 (en) | 2017-11-30 |
US11458194B2 (en) | 2022-10-04 |
AU2017270234B2 (en) | 2023-11-23 |
KR20240103039A (en) | 2024-07-03 |
JP2019516754A (en) | 2019-06-20 |
CN109689089A (en) | 2019-04-26 |
US20210162031A1 (en) | 2021-06-03 |
JP2022133444A (en) | 2022-09-13 |
IL305882A (en) | 2023-11-01 |
KR20230003387A (en) | 2023-01-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220370582A1 (en) | Methods and compositions for treating cancers | |
US20230338494A1 (en) | Methods and compositions for treating cancers | |
US20140109246A1 (en) | Methods of generating xenochimaeric mice with tumor and hematopoietic system from the same heterologous species | |
US20210236633A1 (en) | Methods and compositions for treating cancers | |
Rabe et al. | IL12 abrogates calcineurin-dependent immune evasion during leukemia progression | |
US20240122938A1 (en) | Methods and compositions for treating uveal melanoma | |
US20230270855A1 (en) | Genetically Modified T-Cells and PI3K/AKT Inhibitors For Cancer Treatment | |
WO2023187024A1 (en) | Modified rela protein for inducing interferon expression and engineered immune cells with improved interferon expression | |
Armstrong | The effects of oncolytic Maraba virus (MG1) in malignant melanoma | |
Zhang et al. | Ageing microenvironment mediates lymphocyte carcinogenesis and lymphoma drug resistance: From mechanisms to clinical therapy | |
Evangelou | Dissecting the Mechanism of IFNγ-driven Resistance to Immune Checkpoint Blockade: A Crucial Role for PARP14 | |
Woods | Histone Deacetylases as Targets for Melanoma Immunotherapy |